Asymmetric cyclization processes using unsaturated nitro compounds

ABSTRACT

Disclosed are processes of forming a compound (33), (35) or (37)

CROSS-REFERENCE TO RELATED APPLICATIONS

This application makes reference to and claims the benefit of priorityof an application for “Highly Recyclable Organocatalysis:Enantioselective Michael Addition of 1,3-Diaryl-1,3-propanedione toNitroolefins” filed on May 19, 2009 with the United States Patent andTrademark Office, and there duly assigned Ser. No. 61/179,552. Thecontent of said application filed on May 19, 2009 is incorporated hereinby reference for all purposes in its entirety.

FIELD OF THE INVENTION

The present invention provides asymmetric cyclization processes usingunsaturated nitro compounds. The obtained compounds have a cyclohexaneor a cyclopentane structure with four stereogenic carbon atoms. Using achiral catalyst, cyclic products can be obtained in highenantioselectivities.

BACKGROUND OF THE INVENTION

The asymmetric construction of a stereogenic carbon center with aquaternary carbon atom remains one of the most challenging and demandingtopics in the synthesis of natural products and chiral drugs. Thedevelopment of efficient asymmetric methods to access complex moleculeswith multiple stereogenic centers also continues to be a substantialchallenge in both academic research and industrial applications.

One approach toward these challenges is the use of catalyticenantioselective cascade reactions, which have emerged as powerful toolsto give a rapid increase in molecular complexity from simple and readilyavailable starting materials, thus producing enantioenriched complexcompounds in a single operation. Of the developed strategies forasymmetric tandem reactions, organocatalysis provided an efficientprotocol. The syntheses of substituted cyclohexenes by applying athree-component domino reaction (Enders, D, et al., Nature (2006) 441,861; Enders, D, et al., Angew. Chem. Int. Ed. (2007) 46, 467) and by atwo-component multistep Michael-nitroaldol (Henry) sequence usingpentane-1,5-dial and 2-substituted nitroalkenes (Hayashi, Y, et al,Angew. Chem. Int. Ed. (2007) 46, 4922) have been described.

Although several other elegant organocatalytic tandem reactions havealso been reported recently, the development of new methods for thegeneration of molecules with multiple stereogenic carbons, includingquaternary centers, in a cascade manner remains a big challenge at theforefront of synthetic chemistry. The Michael addition reaction, beingone of the most general and versatile methods for formation of C—C bondsin organic synthesis, has received much attention in the development ofenantioselective catalytic protocols. Domino Michael-Michael (alsocalled “double Michael”) reactions have been explored and demonstratedas a powerful tool in organic synthesis (for a review on double Michaelreactions, see: Ihara, M, & Fukumoto, K, Angew. Chem. Int. Ed. (1993)32, 1010). Efficient asymmetric double Michael processes have beenachieved by relying on the use of chiral auxiliaries and chiralprecursors for stereocontrol. However, the development oforganocatalytic enantioselective versions of the reactions proved to bea challenging task, and there have been very few reports regarding theformation of quaternary and tertiary stereocenters with both excellentenantioselectivity and diastereoselectivity using α,β-unsaturated estersas Michael acceptors.

The nitroaldol reaction, also termed Henry reaction, also represents apowerful C—C bond forming tool, and the resulting nitro alcohol productscan be transformed into a number of nitrogen and oxygen containingderivatives such as nitroalkenes, amino alcohols and amino acids(Palomo, C, et al., Eur. J. Org. Chem. (2007) 2561). In addition tosubstrate-controlled Henry reactions, organocatalytic systems thatprovide good stereoselectivity have been developed in recent years.

It is an object of the present invention to provide a further processthat can be used to form organic molecules with multiple stereogeniccarbon atoms, in particular quaternary carbon centers.

SUMMARY OF THE INVENTION

In a first aspect the invention relates to a process that involvesforming a compound of general formula (33)

In formula (33) R¹ and R² are independently from one another one of asilyl group, an aliphatic group and an alicyclic group. A respectivealiphatic group and an alicyclic group, as well as a silyl group, has amain chain that may have 1 to about 20 carbon atoms and 0 to about 7heteroatoms. Such a heteroatom may be selected from the group consistingof N, O, S, Se and Si. R³ is one of H, a silyl group, an aliphaticgroup, an alicyclic group, an aromatic group, an arylaliphatic group andan arylalicyclic group. A respective silyl group, aliphatic group,alicyclic group, aromatic group, arylaliphatic group or arylalicyclicgroup may have a main chain that may have 1 to about 20 carbon atoms and0 to about 7 heteroatoms. Such a heteroatom is selected from the groupconsisting of N, O, S, Se and Si. R⁴ may be the group —CH═CH—R⁹. In thisgroup R⁹ is one of H, a silyl group, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup. A respective silyl group, aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group may have a main chain that may have1 to about 20 carbon atoms and 0 to about 7 heteroatoms. Such aheteroatom may be selected from the group consisting of N, O, S, Se andSi. R⁴ may also be one of an aromatic group, an arylaliphatic group andan arylalicyclic group. The aromatic, arylaliphatic or arylalicyclicgroup includes a main chain that may have 1 to about 20 carbon atoms and0 to about 7 heteroatoms. Such a heteroatom may be selected from N, O,S, Se and Si. R¹¹ may be H. R¹¹ may also be a silyl group, an aliphaticgroup, an alicyclic group, an aromatic group, an arylaliphatic group oran arylalicyclic group. The aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group includes a main chain that may have1 to about 20 carbon atoms and 0 to about 7 heteroatoms. Such aheteroatom may be selected from N, O, S, Se and Si. R¹¹ may also be oneof a carbonate group —O—C(O)—O—R¹⁷ and a carbamoyl group—O—C(O)—N(R¹⁷)—R¹⁸. In such a carbonate group or carbamoyl group R¹⁷ andR¹⁸ are independent from one another H or one of an aliphatic, aalicyclic, an aromatic, an arylaliphatic, and an arylalicyclic group. Arespective aliphatic, alicyclic, aromatic, arylaliphatic, orarylalicyclic group includes a main chain that may have a length of 1 toabout 20 carbon atoms, which includes 0 to about 6 heteroatoms. Such aheteroatom may be selected from N, O, S, Se and Si. The process includesproviding a first compound of the general formula (1)

The process also includes providing a second compound of the generalformula (2)

The process further includes providing a compound of the general formula(X)

In formula (X) R⁶ is one of H, —OMe, —OH, —OTf, —SH and —NH₂. R⁷ is oneof OH and —N(R⁸)H. In this group R⁸ is one of H, a carbamoyl group, anda thiocarbamoyl group.

represents one of a single and a double bond. Further, the processincludes contacting the first compound of formula (1) and the secondcompound of formula (2) in the presence of the compound of generalformula (X). Thereby a reaction mixture is formed. The process alsoincludes allowing the first and the second compound to undergo—in thepresence of the compound of the general formula (X)—a reaction for asufficient period of time to allow the formation of a compound ofgeneral formula (23)

The compound of formula (23) may then be further reacted to a compoundof formula (33).

In a second aspect the invention relates to a process that involvesforming a compound of general formula (35)

In formula (35) R¹ and R² are independent from one another one of asilyl group, an aliphatic group and an alicyclic group with a main chainthat may have 1 to about 20 carbon atoms. The main chain may furtherhave 0 to about 7 heteroatoms. Such a heteroatom may be selected from N,O, S, Se and Si. R⁴ may be the group —CH═CH—R⁹. In this group R⁹ may beH. It may also be one of a silyl group, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup. A respective silyl group, aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group may have a main chain that has 1 toabout 20 carbon atoms and 0 to about 7 heteroatoms. Such a heteroatommay be selected from the group consisting of N, O, S, Se and Si. R⁴ mayfurther be one of an aromatic group, an arylaliphatic group and anarylalicyclic group. The aromatic, arylaliphatic or arylalicyclic groupincludes a main chain that may have 1 to about 20 carbon atoms and 0 toabout 7 heteroatoms. Such a heteroatom may be selected from N, O, S, Seand Si. R⁵ is one of H, a silyl group, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup with a main chain that may have 1 to about 20 carbon atoms and 0to about 7 heteroatoms. Such a heteroatom may be selected from N, O, S,Se and Si. The process includes providing a first compound of thegeneral formula (4)

In formula (4)

indicates that the bond is in any configuration relative to the C═Cbond, i.e. generally either an E- or a Z-configuration. The process alsoincludes providing a second compound of the general formula (2)

The process further includes providing a compound of the general formula(X)

In formula (X) R⁶ is one of H, —OMe, —OH, —OTf, —SH and —NH₂. R⁷ is oneof OH and —N(R⁸)H. In this group R⁸ is one of H, a carbamoyl group, anda thiocarbamoyl group.

represents one of a single and a double bond. Further, the processincludes contacting the first compound of formula (4) and the secondcompound of formula (2) in the presence of the compound of generalformula (X). Thereby a reaction mixture is formed. The process alsoincludes allowing the first and the second compound to undergo—in thepresence of the compound of the general formula (X)—a reaction for asufficient period of time to allow the formation of a compound ofgeneral formula (35).

In a third aspect the invention relates to a process that involvesforming a compound of general formula (35)

In formula (37) R¹ and R² are independent from one another one of asilyl group, an aliphatic group and an alicyclic group. A respectivealiphatic group and an alicyclic group, as well as a silyl group, has amain chain that may have 1 to about 20 carbon atoms and 0 to about 7heteroatoms. Such a heteroatom is selected from the group consisting ofN, O, S, Se and Si. R³ is one of a silyl group, an aliphatic group, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group. A respective silyl group, aliphatic group,alicyclic group, aromatic group, arylaliphatic group or arylalicyclicgroup may have a main chain that has 1 to about 20 carbon atoms and 0 toabout 7 heteroatoms. Such a heteroatom may be selected from the groupconsisting of N, O, S, Se and Si. R⁴ may be the group —CH═CH—R⁹. In thisgroup R⁹ is one of H, a silyl group, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup. A respective silyl group, aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group may have a main chain that has 1 toabout 20 carbon atoms and 0 to about 7 heteroatoms. Such a heteroatommay be selected from the group consisting of N, O, S, Se and Si. R⁴ mayalso be one of an aromatic group, an arylaliphatic group and anarylalicyclic group. The aromatic, arylaliphatic or arylalicyclic groupincludes a main chain that may have 1 to about 20 carbon atoms and 0 toabout 7 heteroatoms. Such a heteroatom may be selected from N, O, S, Seand Si. R¹¹ may be H. R¹¹ may also be a silyl group, an aliphatic group,an alicyclic group, an aromatic group, an arylaliphatic group or anarylalicyclic group. The aliphatic, alicyclic, aromatic, arylaliphaticor arylalicyclic group includes a main chain that has 1 to about 20carbon atoms and 0 to about 7 heteroatoms. Such a heteroatom may beselected from N, O, S, Se and Si. R¹¹ may also be one of a carbonategroup —O—C(O)—O—R¹⁷ and a carbamoyl group —O—C(O)—N(R¹⁷)—R¹⁸. In such acarbonate group or carbamoyl group R¹⁷ and R¹⁸ are independent from oneanother H or one of an aliphatic, a alicyclic, an aromatic, anarylaliphatic, and an arylalicyclic group. A respective aliphatic, aalicyclic, an aromatic, an arylaliphatic, and an arylalicyclic groupincludes a main chain of a length of 1 to about 20 carbon atoms, whichmay include 0 to about 6 heteroatoms. Such a heteroatom may be selectedfrom N, O, S, Se and Si. The process includes providing a first compoundof the general formula (6)

The process also includes providing a second compound of the generalformula (2)

The process further includes providing a compound of the general formula(X)

In formula (X) R⁶ is one of H, —OMe, —OH, —OTf, —SH and —NH₂. R⁷ is oneof OH and —N(R⁸)H. In this group R⁸ is one of H, a carbamoyl group, anda thiocarbamoyl group.

represents one of a single and a double bond. Further, the processincludes contacting the first compound of formula (1) and the secondcompound of formula (2) in the presence of the compound of generalformula (X). Thereby a reaction mixture is formed. The process alsoincludes allowing the first and the second compound to undergo—in thepresence of the compound of the general formula (X)—a reaction for asufficient period of time to allow the formation of a compound ofgeneral formula (27)

The compound of formula (27) may then be further reacted to a compoundof formula (37).

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood with reference to the detaileddescription when considered in conjunction with the non-limitingexamples and the accompanying drawings.

FIG. 1A depicts a scheme on an asymmetric tandem Michael-Henry reactionusing exemplary Cinchona alkaloid catalyst VI, yielding a cyclohexaneproduct. FIG. 1B depicts a scheme on an asymmetric domino double Michaelreaction using exemplary Cinchona alkaloid catalyst VI, yielding acyclopentane product. FIG. 1C depicts a scheme on an asymmetric dominoMichael-Henry reaction using exemplary Cinchona alkaloid catalyst VI,yielding a cyclopentane product.

FIG. 2 depicts structures of exemplary Cinchona alkaloid catalysts thatcan be used in the processes of the invention.

FIG. 3 depicts examples of organocatalytic Tandem Michael-HenryReactions of ethyl 2-acetyl-5-oxohexanoate 1a and trans-β-Nitrostyrene2a. Unless otherwise specified, all of the reactions were carried outusing 1a (0.6 mmol, 1.5 equiv) and 2a (0.4 mmol, 1.0 equiv) with 10 mol% of catalyst at room temperature (23° C.). b: Isolated yields. c:Determined by crude NMR. d: Determined by chiral HPLC analysis (majorisomer). e: Reaction at 4° C. f: 15 mol % of catalyst was used. g: 1a(0.4 mmol, 1.0 equiv) and 2a (0.6 mmol, 1.5 equiv) were used.

FIG. 4 illustrates an example of a tandem Michael-Henry reaction ofdiketo ester 1a and nitroolefin (2) Catalyzed by Catalyst VI.

FIG. 5 shows examples of a tandem Michael-Henry reactions of 1a with 2kand 1b/1c with 2a.

FIG. 6 shows examples and data of organocatalytic domino double Michaelreactions of ethyl 2-acetyl-5-oxohexanoate 4a (E:Z) 6:1) andtrans-β-Nitrostyrene 2a. Unless otherwise specified, all the reactionswere carried out using 4a (0.3 mmol, 1.0 equiv) and 2a (0.45 mmol, 1.5equiv) with 15 mol % of catalyst at room temperature (22° C.). b:Isolated yields. c: Determined by NMR and HPLC analysis. d: Determinedby chiral HPLC analysis (major isomer). e: Reaction at 0° C. f: Catalyst(10 mol %) was used. g: 4a (0.45 mmol, 1.5 equiv) and 2a (0.3 mmol, 1.0equiv) were used.

FIG. 7 depicts examples and data of a domino double Michael reaction ofethyl 2-acetyl-5-oxohexanoate 4a (E:Z) 6:1) and Nitroolefins (2)Catalyzed by Catalyst VI. Unless otherwise specified, the reactions werecarried out using 4a (0.3 mmol, 1.0 equiv) and 2 (0.45 mmol, 1.5 equiv)in the presence of 15 mol % of VI at room temperature in diethyl ether(0.4 mL) (see the Examples). b: Isolated yields. c: Determined by NMRand HPLC analysis. d: Determined by chiral HPLC analysis (major isomer).e: 20 mol % catalyst and 2.0 equiv of 2 were used.

FIG. 8 illustrates domino double Michael reactions of 4a with 2a (E:Z)10:1) and 4b with 2a/2k.

FIG. 9 depicts the X-ray crystal structure of compound 5g.

FIG. 10 illustrates schematically an organocatalytic synthesis ofcycloalkanes using the tandem Michael-Henry reactions strategy.

FIG. 11 depicts examples and data of domino Michael-Henry reactions ofethyl 2-acetyl-4-oxo-4-phenylbutanoate (6a) and trans-β-Nitrostyrene.Unless otherwise specified, all the reactions were carried out using 6(1.0 mmol, 2.0 equiv) and 2a (0.5 mmol, 1.0 equiv) with 10 mol % ofcatalysts at room temperature. b: Isolated yields. c: Determined bychiral HPLC analysis. d: Reaction at 4° C. e: No reaction. f: Notapplicable.

FIG. 12 shows examples and data of domino Michael-Henry reactions ofethyl 2-acetyl-4-oxo-4-phenylbutanoate (6d) and nitroolefins catalyzedby catalyst VI. All the reactions were carried out using 6d (1.0 mmol,2.0 equiv) and 2 (0.5 mmol, 1.0 equiv) in the presence of 10 mol % of VIat 4° C. with toluene (0.5 mL). b: Isolated yields. c: Determined bychiral HPLC analysis.

FIG. 13 depicts organocatalytic domino Michael-Henry reactions oftrisubstituted carbon nucleophiles (6b or 6c) to trans-β-NitrostyreneCatalyzed by Catalyst VI.

FIG. 14 depicts the X-ray crystal structure of compound 7f.

FIG. 15 illustrates the proposed action of the catalyst in a tandemMichael-Henry reaction yielding a cyclohexane compound.

FIG. 16 illustrates the proposed action of the catalyst in a tandemdouble Michael reaction yielding a cyclopentane compound.

FIG. 17 illustrates the proposed action of the catalyst in a dominoMichael-Henry reaction yielding a cyclopentane compound.

FIG. 18A depicts a ¹H NMR spectrum and FIG. 18B a ¹³C NMR spectrum ofcompound 3a.

FIG. 19 depicts a ¹H NMR spectrum (A) and a ¹³C NMR spectrum (B) ofcompound 3b.

FIG. 20 depicts a ¹H NMR spectrum (A) and a ¹³C NMR spectrum (B) ofcompound 3c.

FIG. 21A depicts a ¹H NMR spectrum and FIG. 21B a ¹³C NMR spectrum ofcompound 3d.

FIG. 22 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3e.

FIG. 23 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3f.

FIG. 24 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3g.

FIG. 25 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3h.

FIG. 26 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3i.

FIG. 27 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3j.

FIG. 28 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3k.

FIG. 29 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3l.

FIG. 30 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 3m.

FIG. 31 depicts an HPLC spectrum of a racemic mixture of compound 3a (A)in comparison to the obtained product 3a (B).

FIG. 32 depicts an HPLC spectrum of a racemic mixture of compound 3b (A)in comparison to the obtained product 3b (B).

FIG. 33 depicts an HPLC spectrum of a racemic mixture of compound 3c (A)in comparison to the obtained product 3c (B).

FIG. 34 depicts an HPLC spectrum of a racemic mixture of compound 3d (A)in comparison to the obtained product 3d (B).

FIG. 35 depicts an HPLC spectrum of a racemic mixture of compound 3e(A), and in comparison the obtained product 3e (B).

FIG. 36 depicts an HPLC spectrum of a racemic mixture of compound 3f(A), and in comparison the obtained product 3f (B).

FIG. 37 depicts an HPLC spectrum of a racemic mixture of compound 3g(A), and in comparison the obtained product 3g (B).

FIG. 38 depicts an HPLC spectrum of a racemic mixture of compound 3h(A), and in comparison the obtained product 3h (B).

FIG. 39 depicts an HPLC spectrum of a racemic mixture of compound 3i(A), and in comparison the obtained product 3i (B).

FIG. 40 depicts an HPLC spectrum of a racemic mixture of compound 3j(A), and in comparison the obtained product 3j (B).

FIG. 41 depicts an HPLC spectrum of a racemic mixture of compound 3k(A), and in comparison the obtained product 3k (B).

FIG. 42 depicts an HPLC spectrum of a racemic mixture of compound 3l(A), and in comparison the obtained product 3l (B).

FIG. 43 depicts an HPLC spectrum of a racemic mixture of compound 3m(A), and in comparison the obtained product 3m (B).

FIG. 44 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5a.

FIG. 45 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5b.

FIG. 46 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5c.

FIG. 47 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5d.

FIG. 48 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5e.

FIG. 49 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5g.

FIG. 50 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5l.

FIG. 51 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5m.

FIG. 52 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5n.

FIG. 53 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5o.

FIG. 54 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5p.

FIG. 55 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5q.

FIG. 56 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5r.

FIG. 57 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5s.

FIG. 58 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 5t.

FIG. 59 depicts an HPLC spectrum of a racemic mixture of compound 5a(A), and in comparison the obtained product 5a (B).

FIG. 60 depicts an HPLC spectrum of a racemic mixture of compound 5b(A), and in comparison the obtained product 5b (B).

FIG. 61 depicts an HPLC spectrum of a racemic mixture of compound 5c(A), and in comparison the obtained product 5c (B).

FIG. 62 depicts an HPLC spectrum of a racemic mixture of compound 5d(A), and in comparison the obtained product 5d (B).

FIG. 63 depicts an HPLC spectrum of a racemic mixture of compound 5e(A), and in comparison the obtained product 5e (B).

FIG. 64 depicts an HPLC spectrum of a racemic mixture of compound 5g(A), and in comparison the obtained product 5g (B).

FIG. 65 depicts an HPLC spectrum of a racemic mixture of compound 5l(A), and in comparison the obtained product 5l (B).

FIG. 66 depicts an HPLC spectrum of a racemic mixture of compound 5m(A), and in comparison the obtained product 5m (B).

FIG. 67 depicts an HPLC spectrum of a racemic mixture of compound 5n(A), and in comparison the obtained product 5n (B).

FIG. 68 depicts an HPLC spectrum of a racemic mixture of compound 5o(A), and in comparison the obtained product 5o (B).

FIG. 69 depicts an HPLC spectrum of a racemic mixture of compound 5p(A), and in comparison the obtained product 5p (B).

FIG. 70 depicts an HPLC spectrum of a racemic mixture of compound 5q(A), and in comparison the obtained product 5q (B).

FIG. 71 depicts an HPLC spectrum of a racemic mixture of compound 5r(A), and in comparison the obtained product 5r (B).

FIG. 72 depicts an HPLC spectrum of a racemic mixture of compound 5s(A), and in comparison the obtained product 5s (B).

FIG. 73 depicts an HPLC spectrum of a racemic mixture of compound 5t(A), and in comparison the obtained product 5t (B).

FIG. 74A depicts a ¹H NMR spectrum and FIG. 74B a ¹³C NMR spectrum ofcompound 7a.

FIG. 75 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7w.

FIG. 76 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7b.

FIG. 77 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7t.

FIG. 78 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7c.

FIG. 79 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7e.

FIG. 80 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7g.

FIG. 81 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7q.

FIG. 82 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7p.

FIG. 83 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7n.

FIG. 84 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7r.

FIG. 85 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7j.

FIG. 86 depicts an HPLC spectrum of a racemic mixture of compound 7a(A), and in comparison the obtained product 7a (B).

FIG. 87 depicts an HPLC spectrum of a racemic mixture of compound 7w(A), and in comparison the obtained product 7w (B).

FIG. 88 depicts an HPLC spectrum of a racemic mixture of compound 7b(A), and in comparison the obtained product 7b (B).

FIG. 89 depicts an HPLC spectrum of a racemic mixture of compound 7t(A), and in comparison the obtained product 7t (B).

FIG. 90 depicts an HPLC spectrum of a racemic mixture of compound 7c(A), and in comparison the obtained product 7c (B).

FIG. 91 depicts an HPLC spectrum of a racemic mixture of compound 7e(A), and in comparison the obtained product 7e (B).

FIG. 92 depicts an HPLC spectrum of a racemic mixture of compound 7g(A), and in comparison the obtained product 7g (B).

FIG. 93 depicts an HPLC spectrum of a racemic mixture of compound 7p(A), and in comparison the obtained product 7p (B).

FIG. 94 depicts an HPLC spectrum of a racemic mixture of compound 7q(A), and in comparison the obtained product 7q (B).

FIG. 95 depicts an HPLC spectrum of a racemic mixture of compound 7n(A), and in comparison the obtained product 7n (B).

FIG. 96 depicts an HPLC spectrum of a racemic mixture of compound 7r(A), and in comparison the obtained product 7r (B).

FIG. 97 depicts an HPLC spectrum of a racemic mixture of compound 7j(A), and in comparison the obtained product 7j (B).

FIG. 98 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7s.

FIG. 99 depicts ¹H NMR (A) and ¹³C NMR (B) spectra of compound 7x.

FIG. 100 depicts an HPLC spectrum of a racemic mixture of compound 7s(A), and in comparison the obtained product 7s (B).

FIG. 101 depicts an HPLC spectrum of a racemic mixture of compound 7x(A), and in comparison the obtained product 7x (B).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to processes that involve cyclization reactions.The cyclization reactions proceed in an asymmetric fashion such that anasymmetric cyclization process is carried out if an asymmetric compoundis used as further explained below. This asymmetric compound is, withoutbeing bound by theory, thought to act as a catalyst. The processes usean unsaturated nitro compound and a 2-substituted 3-ketoester or acorresponding aldehyde (i.e. a 2-substituted 2-formyl-ester) asreactants. The processes can, without being bound by theory, be taken asinvolving a Michael reaction. In the reaction that occurs in the processof the invention the compound that can be taken to define the Michaelacceptor is an alkene substituted with a group R⁴ and with a nitrogroup.

Accordingly, a compound of the general formula (2) is used in a processof the invention:

In formula (2) R⁴ may in some embodiments be the group —CH═CH—R⁹. Inthis group R⁹ may be H. R⁹ may also be one of a silyl group, analiphatic group, an alicyclic group, an aromatic group, an arylaliphaticgroup and an arylalicyclic group. A respective aliphatic, alicyclic,aromatic or arylaliphatic moiety of R⁹ typically has a main chain ofabout 1 to about 30 carbon atoms, such as 2 to about 30 carbon atoms or3 to about 30 carbon atoms, including about 1 to about 25 carbon atoms,about 1 to about 20 carbon atoms, about 2 to about 20 carbon atoms,about 1 to about 15 carbon atoms, about 2 to about 15 carbon atoms,about 3 to about 15 carbon atoms, about 1 to about 10 carbon atoms,about 2 to about 10 carbon atoms or about 3 to about 10 carbon atoms,such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24 or 25 carbon atoms. The main chain of thealiphatic, alicyclic, aromatic or arylaliphatic moiety further has 0 toabout 6, e.g. 0 to about 5 or 0 to about 4, such as 0, 1, 2, 3, 4, 5 or6 heteroatoms. A respective heteroatom may be one of N, O, S, Se and Si.

A respective silyl group may be represented as

Each of R⁴¹, R⁴² and R⁴³ may be an independently selected aliphatic,alicyclic, aromatic, arylaliphatic or arylalicyclic group. A respectivealiphatic, alicyclic, aromatic or arylaliphatic group may have a mainchain of about 1 to about 30 carbon atoms, such as 2 to about 30 carbonatoms or 3 to about 30 carbon atoms, including about 1 to about 25carbon atoms, about 1 to about 20 carbon atoms, about 2 to about 20carbon atoms, about 1 to about 15 carbon atoms, about 2 to about 15carbon atoms, about 3 to about 15 carbon atoms, about 1 to about 10carbon atoms, about 2 to about 10 carbon atoms or about 3 to about 10carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 carbon atoms. The main chain ofthe aliphatic, alicyclic, aromatic or arylaliphatic moiety may furtherhave 0 to about 6, e.g. 0 to about 5 or 0 to about 4, such as 0, 1, 2,3, 4, 5 or 6 heteroatoms. A respective heteroatom may be one of N, O, S,Se and Si.

The term “aliphatic” means, unless otherwise stated, a straight orbranched hydro-carbon chain, which may be saturated or mono- orpoly-unsaturated and include heteroatoms. The term “heteroatom” as usedherein means an atom of any element other than carbon or hydrogen. Anunsaturated aliphatic group contains one or more double and/or triplebonds (alkenyl or alkinyl moieties). The branches of the hydrocarbonchain may include linear chains as well as non-aromatic cyclic elements.The hydrocarbon chain, which may, unless otherwise stated, be of anylength, and contain any number of branches. Typically, the hydrocarbon(main) chain includes 1 to 5, to 10, to 15 or to 20 carbon atoms.Examples of alkenyl radicals are straight-chain or branched hydrocarbonradicals which contain one or more double bonds. Alkenyl radicalsgenerally contain about two to about twenty carbon atoms and one ormore, for instance two, double bonds, such as about two to about tencarbon atoms, and one double bond. Alkynyl radicals normally containabout two to about twenty carbon atoms and one or more, for example two,triple bonds, such as two to ten carbon atoms, and one triple bond.Examples of alkynyl radicals are straight-chain or branched hydrocarbonradicals which contain one or more triple bonds. Examples of alkylgroups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, the n isomers of these radicals, isopropyl, isobutyl,isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3 dimethylbutyl. Both themain chain as well as the branches may furthermore contain heteroatomsas for instance N, O, S, Se or Si or carbon atoms may be replaced bythese heteroatoms.

The term “alicyclic” may also be referred to as “cycloaliphatic” andmeans, unless stated otherwise, a non-aromatic cyclic moiety (e.g.hydrocarbon moiety), which may be saturated or mono- orpoly-unsaturated. The cyclic hydrocarbon moiety may also include fusedcyclic ring systems such as decalin and may also be substituted withnon-aromatic cyclic as well as chain elements. The main chain of thecyclic hydrocarbon moiety may, unless otherwise stated, be of any lengthand contain any number of non-aromatic cyclic and chain elements.Typically, the hydrocarbon (main) chain includes 3, 4, 5, 6, 7 or 8 mainchain atoms in one cycle. Examples of such moieties include, but are notlimited to, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Boththe cyclic hydrocarbon moiety and, if present, any cyclic and chainsubstituents may furthermore contain heteroatoms, as for instance N, O,S, Se or Si, or a carbon atom may be replaced by these heteroatoms. Theterm “alicyclic” also includes cycloalkenyl moieties that areunsaturated cyclic hydrocarbons, which generally contain about three toabout eight ring carbon atoms, for example five or six ring carbonatoms. Cycloalkenyl radicals typically have a double bond in therespective ring system. Cycloalkenyl radicals may in turn besubstituted. Examples of such moieties include, but are not limited to,cyclohexenyl, cyclooctenyl or cyclodecenyl.

In contrast thereto, the term “aromatic” means an at least essentiallyplanar cyclic hydrocarbon moiety of conjugated double bonds, which maybe a single ring or include multiple condensed (fused) or covalentlylinked rings, for example, 2, 3 or 4 fused rings. The term aromatic alsoincludes alkylaryl. Typically, the hydrocarbon (main) chain includes 5,6, 7 or 8 main chain atoms in one cycle. Examples of such moietiesinclude, but are not limited to, cyclopentadienyl, phenyl, napthalenyl-,[10]annulenyl-(1,3,5,7,9-cyclodecapentaenyl-), [12]annulenyl-,[8]annulenyl-, phenalene (perinaphthene), 1,9-dihydropyrene, chrysene(1,2-benzophenanthrene). An example of an alkylaryl moiety is benzyl.The main chain of the cyclic hydrocarbon moiety may, unless otherwisestated, be of any length and contain any number of heteroatoms, as forinstance N, O and S. Such a heteroaromatic moiety may for example be a5- to 7-membered unsaturated heterocycle which has one or moreheteroatoms from the series O, N, S. Examples of such heteroaromaticmoieties (which are known to the person skilled in the art) include, butare not limited to, furanyl-, thiophenyl-, naphtyl-, naphthofuranyl-,anthrathiophenyl-, pyridinyl-, pyrrolyl-, quinolinyl,naphthoquinolinyl-, quinoxalinyl-, indolyl-, benzindolyl-, imidazolyl-,oxazolyl-, oxoninyl-, oxepinyl-, benzoxepinyl-, azepinyl-, thiepinyl-,selenepinyl-, thioninyl-, azecinyl-, (azacyclodecapentaenyl-),diazecinyl-, azacyclododeca-1,3,5,7,9,11-hexaene-5,9-diyl-, azozinyl-,diazocinyl-, benzazocinyl-, azecinyl-, azaundecinyl-,thia[11]annulenyl-, oxacyclotrideca-2,4,6,8,10,12-hexaenyl- ortriazaanthracenyl-moieties.

By the term “arylaliphatic” is meant a hydrocarbon moiety, in which oneor more aromatic moieties are substituted with one or more aliphaticgroups. Thus the term “arylaliphatic” also includes hydrocarbonmoieties, in which two or more aryl groups are connected via one or morealiphatic chain or chains, respectively, of any length, for instance amethylene group. Typically, the hydrocarbon (main) chain includes 5, 6,7 or 8 main chain atoms in each ring of the aromatic moiety. Examples ofarylaliphatic moieties such as alkylaryl moieties include, but are notlimited, to 1-ethyl-naphthalene, 1,1′-methylenebis-benzene,9-isopropylanthracene, 1,2,3-trimethyl-benzene, 4-phenyl-2-buten-1-ol,7-chloro-3-(1-methylethyl)-quinoline, 3-heptyl-furan,6-[2-(2,5-diethyl-phenyl)ethyl]-4-ethyl-quinazoline or,7,8-dibutyl-5,6-diethyl-isoquinoline.

Each of the terms “aliphatic”, “alicyclic”, “aromatic” and“arylaliphatic” as used herein is meant to include both substituted andunsubstituted forms of the respective moiety. Substituents my be anyfunctional group, as for example, but not limited to, amino, amido,azido, carbonyl, carboxyl, cyano, isocyano, dithiane, halogen, hydroxyl,nitro, organometal, organoboron, seleno, silyl, silano, sulfonyl, thio,thiocyano, trifluoromethyl sulfonyl, p-toluenesulfonyl,bromobenzene-sulfonyl, nitrobenzenesulfonyl, and methanesulfonyl.

An aliphatic, alicyclic, aromatic or arylaliphatic moiety may carryfurther moieties such as side chains. Such further moieties may be analiphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic groupthat typically is of a main chain length of 1 to about 10, to about 15or to about 20 carbon atoms. These further moieties may also carryfunctional groups (supra).

R⁴ may also be an aromatic group, an arylaliphatic group or anarylalicyclic group. The aromatic, arylaliphatic or arylalicyclic groupincludes a main chain that typically has 1 to about 30 carbon atoms,such as 2 to about 30 carbon atoms or 3 to about 30 carbon atoms,including about 1 to about 20 carbon atoms, about 2 to about 20 carbonatoms, about 3 to about 20 carbon atoms, about 1 to about 15 carbonatoms, about 2 to about 15 carbon atoms, about 1 to about 10 carbonatoms, about 2 to about 10 carbon atoms or about 1 to about 8 carbonatoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19 or 20 carbon atoms. The respective main chain of thearomatic, arylaliphatic or arylalicyclic moiety of R⁴ may have 0 toabout 8 heteroatoms, such as 0 to about 7 or 0 to about 6, e.g. 0 toabout 5 or 0 to about 4, such as 0, 1, 2, 3, 4, 5 or 6 heteroatoms. Arespective heteroatom may be one of N, O, S, Se and Si.

In one process according to the invention the compound of the generalformula (2) is contacted with a compound of general formula (1)

In formula (1) R¹ and R² may independently from one another be a silylgroup (supra), an aliphatic group or an alicyclic group. A respectivesilyl group (supra), aliphatic or alicyclic group has a main chain thattypically includes 1 to about 30 carbon atoms, such as 2 to about 30carbon atoms or 3 to about 30 carbon atoms, including about 1 to about20 carbon atoms, about 2 to about 20 carbon atoms, about 3 to about 20carbon atoms, about 1 to about 15 carbon atoms, about 2 to about 15carbon atoms, about 1 to about 10 carbon atoms, about 2 to about 10carbon atoms or about 1 to about 8 carbon atoms, such as 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.The respective main chain of the aliphatic group or alicyclic group ofR¹ and/or R² (see above for a silyl group) may have 0 to about 8heteroatoms, such as 0 to about 7 or 0 to about 6, e.g. 0 to about 5 or0 to about 4, such as 0, 1, 2, 3, 4, 5 or 6 heteroatoms. Such aheteroatom may be selected from N, O, S, Se and Si.

R³ in formula (1) may be a silyl group, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group or an arylalicyclicgroup. A respective silyl group may be as defined above. A correspondingaliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group mayhave a main chain that typically includes 1 to about 30 carbon atoms,such as 2 to about 30 carbon atoms or 3 to about 30 carbon atoms,including about 1 to about 20 carbon atoms, about 2 to about 20 carbonatoms, about 3 to about 20 carbon atoms, about 1 to about 15 carbonatoms, about 2 to about 15 carbon atoms, about 1 to about 10 carbonatoms, about 2 to about 10 carbon atoms or about 1 to about 8 carbonatoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19 or 20 carbon atoms. The respective main chain of thealiphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group ofR³ (see above for a silyl group) may have 0 to about 8 heteroatoms, suchas 0 to about 7 or 0 to about 6, e.g. 0 to about 5 or 0 to about 4, suchas 0, 1, 2, 3, 4, 5 or 6 heteroatoms. Such a heteroatom may be selectedfrom N, O, S, Se and Si.

In a further process according to the invention the compound of thegeneral formula (2) is contacted with a compound of general formula (4)

In formula (4) R¹ and R² are as defined above. R⁵ may in someembodiments be H. R⁵ may in some embodiments also be a silyl group, asdefined above. In some embodiments R⁵ may be an aliphatic group, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group. A respective aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group may have a main chain that thatincludes 1 to about 30 carbon atoms, such as 2 to about 30 carbon atomsor 3 to about 30 carbon atoms, including about 1 to about 20 carbonatoms, about 2 to about 20 carbon atoms, about 3 to about 20 carbonatoms, about 1 to about 15 carbon atoms, about 2 to about 15 carbonatoms, about 1 to about 10 carbon atoms, about 2 to about 10 carbonatoms or about 1 to about 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Themain chain of the aliphatic, alicyclic, aromatic, arylaliphatic orarylalicyclic group of R⁵ (see above for a silyl group) may have 0 toabout 8 heteroatoms, such as 0 to about 7 or 0 to about 6, e.g. 0 toabout 5 or 0 to about 4, such as 0, 1, 2, 3, 4, 5 or 6 heteroatoms. Sucha heteroatom may be selected from N, O, S, Se and Si.

In a further process according to the invention the compound of thegeneral formula (2) is contacted with a compound of general formula (6)

In formula (6) R¹ to R³ are as defined above. In the following thecompound of general formula (1), of general formula (4) or of generalformula (6), which is reacted with the nitro compound of formula (2), isalso called the first compound. The compound of formula (2) is alsocalled the second compound. Accordingly, if the reaction is taken to bedefined in terms of a Michael reaction or a Michael reaction step, theMichael donor is herein also referred to as the first compound and theMichael acceptor as the second compound.

The second compound, i.e. the compound of the general formula (2) andthe first compound, i.e. the compound of general formula (1), thecompound of general formula (4) or the compound of general formula (6),respectively, are allowed to react in the presence of a quinine-based ora quinidine-based compound. The compound is of the general formula (X)

In formula (X) R⁶ may in some embodiments be H. R⁶ may also be —OMe,—OH, —OTf, —SH or —NH₂. R⁷ may be —OH and —N(R⁸)H. The respective moietyR⁸ may be H, a carbamoyl group or a thiocarbamoyl group. A respectivecarbamoyl group may be represented as —C(O)—N(R²¹)—R¹² and a respectivethiocarbamoyl group as —C(S)—N(R²¹)—R¹². R²¹ and R¹² in the carbamoylgroup and the thiocarbamoyl group, respectively, are independent fromone another H or one of an aliphatic, an alicyclic, an aromatic, anarylaliphatic, and an arylalicyclic group. A respective aliphatic,alicyclic, aromatic, arylaliphatic or arylcycloaliphatic group may havea main chain that typically includes 1 to about 30 carbon atoms, such as2 to about 30 carbon atoms or 3 to about 30 carbon atoms, includingabout 1 to about 20 carbon atoms, about 2 to about 20 carbon atoms,about 3 to about 20 carbon atoms, about 1 to about 15 carbon atoms,about 2 to about 15 carbon atoms, about 1 to about 10 carbon atoms,about 2 to about 10 carbon atoms or about 1 to about 8 carbon atoms,such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19 or 20 carbon atoms. The respective main chain of the aliphatic,alicyclic, aromatic, arylaliphatic or arylalicyclic group of R²¹ and/orR¹² may have 0 to about 8 heteroatoms, such as 0 to about 7 or 0 toabout 6, e.g. 0 to about 5 or 0 to about 4, such as 0, 1, 2, 3, 4, 5 or6 heteroatoms. A respective heteroatom may be selected from N, O, S, Seand Si.

in general formula (X) represents a single or a double bond. Hence, insome embodiments

in the context of the structural formula represents —CH₂—CH₃, and insome embodiments —CH═CH₂. Illustrative examples of moieties R⁶ and R⁷can be taken from FIG. 2.

A number of corresponding compounds, such as cinchonidine, cinchonine,quinine or quinidine are commercially available. Modifications such ashydrations (e.g. dihydrocinchonidine) or conversions of functionalgroups can be carried out using standard procedures available in theart.

The first compound, the second compound and the compound of formula (X)may be used in any ratio relative to each other. For example, thecompounds of formulas (1), (2) and (X) may be used in any ratio relativeto each other. In some embodiments the first compound, e.g. compound(1), is used in an about similar, including about equal amount or highercompared to the amount of compound (2). In some embodiments compound (2)is used in an at least about equal amount or higher when compared to theamount of the first compound, e.g. compound (1). Accordingly the firstcompound may be provided in excess to the second compound. The firstcompound may for example be provided in a molar amount of about1.1-fold, about 1.2-fold, about 1.5-fold, about 2-fold, about 2.5-fold,about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold or about5-fold in comparison to the molar amount of the second compound.

In some embodiments compound (X) is used in an about similar or loweramount than the amount of one the first and the second compound, e.g. ofcompound (1) and compound (2). Compound (2) may for example be used inexcess to compound (1). Compound (X) may then for instance be used in anabout similar or lower amount relative to the amount of the firstcompound, e.g. compound (1). It may also be used in an about similar orlower amount relative to the amount of compound (2). In some embodimentscompound (X) is used in a catalytic amount. The term “catalytic amount”as also used in the art refers to a substoichiometric amount relative toa reactant, in particular relative to a reactant that is used in a loweramount than another reactant. The catalytic amount of a particularcompound (X) varies according to the concentration of the first and thesecond compound, e.g. compounds (1) and (2), as well as to reactionconditions such as temperature and time. As used herein, a catalyticamount means from about 0.0001 to about 90 mole percent relative to areactant, such as from about 0.001 to about 50 mole percent, from about0.001 to about 25 mole percent, from about 0.01 to about 10 molepercent, or from about 0.1 to about 5 mole percent relative to areactant. In some embodiments the respective mole percent value isdetermined relative to that amount of the first or the second compound,e.g. compounds (1) and (2) that is lower. If in such an embodimentcompound (2) is used in an excess relative to the first compound, e.g.compound (1), the mole percent value of the amount of compound (X) isdetermined relative to the amount of compound (1). The above saidapplies mutatis mutandis to the compounds of formulas (4), (2) and (X),and to the compounds of formulas (6), (2) and (X), where these compoundsare used in a process according to the invention. For example, in someembodiments the compound of formula (X) is used in a substoichiometricamount relative to the compound of formula (4) or to the compound offormula (6), respectively.

A reaction mixture may be formed by contacting the second compound, i.e.the compound of formula (2), and the first compound, i.e. the compoundof either formula (1), formula (4) or formula (6), in the presence ofthe compound of formula (X). The reaction mixture may be formed at anytemperature at which the three compounds, i.e. either the two reactantsof formulae (1) and (2), the two reactants of formulae (4) and (2) orthe two reactants of formulae (6) and (2), and the compound of formula(X) are at least essentially stable enough to undergo a cyclizationreaction. The reaction mixture may be formed at a temperature from about−200° C. to about 50° C., including from about −180° C. to about 40° C.,from about −180° C. to about 30° C., from about −160° C. to about 50°C., from about −160° C. to about 40° C., from about −40° C. to about 40°C., from about −20° C. to about 40° C., from about −40° C. to about 30°C. or from about 0° C. to about 30° C., such as ambient temperature,e.g. about 18° C. or about 22° C. The first compound and the nitrocompound of formula (2) may be allowed to react in the reaction mixtureat the same temperature. In some embodiments the reaction temperature isaltered, such as increased or lowered. The reaction may be allowed toproceed at a temperature from about −200° C. to about 50° C., includingfrom about −180° C. to about 40° C., from about −180° C. to about 30°C., from about −160° C. to about 50° C., from about −160° C. to about40° C., from about −100° C. to about 40° C., from about −40° C. to about40° C., from about −20° C. to about 40° C., from about −20° C. to about30° C. or from about 0° C. to about 30° C., such as ambient temperature,e.g. about 18° C. or about 22° C.

The present process of the invention may in some embodiments be carriedout in the absence of any solvent. In some embodiments forming thereaction mixture includes adding a liquid. Thereby the first compound,the second compound and the compound of formula (X) may be dissolved inthe liquid. Accordingly, the present process of the invention may becarried out in the liquid phase. Any solvent may be used, as long as thecompounds can undergo a cyclization reaction therein to a desiredextent. Solvents used may be polar or non-polar liquids, includingaprotic non-polar liquids. Examples of non-polar liquids include, butare not limited to mineral oil, hexane, heptane, cyclohexane, benzene,toluene, dichloromethane, chloroform, carbon tetrachloride, carbondisulfide, and a non-polar ionic liquid. Examples of a non-polar ionicliquid include, but are not limited to, 1-ethyl-3-methylimidazoliumbis[(trifluoromethyl)sulfonyl]amide bis(triflyl)-amide,1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]amidetrifluoroacetate, 1-butyl-3-methylimidazolium hexafluorophosphate,1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide,1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide,trihexyl(tetradecyl)-phosphonium bis[oxalato(2-)]borate,1-hexyl-3-methyl imidazolium tris(pentafluoroethyl)trifluoro-phosphate,1-butyl-3-methyl-imidazolium hexafluorophosphate,tris(pentafluoroethyl)trifluoro-phosphate,trihexyl(tetradecyl)phosphonium,N″-ethyl-N,N,N′,N′-tetramethylguanidinium, 1-butyl-1-methylpyrrolidiniumtris(pentafluoroethyl) trifluorophosphane, 1-butyl-1-methylpyrrolidiniumbis(trifluoromethylsulfonyl) imide, 1-butyl-3-methyl imidazoliumhexafluorophosphate, 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide and 1-n-butyl-3-methylimidazolium.

A polar solvent, such as a polar protic solvent, can be a solvent thathas, for example, a hydrogen atom bound to an oxygen as in a hydroxylgroup or a nitrogen as in an amine group. More generally, any molecularsolvent which contains dissociable H⁺, such as hydrogen fluoride, iscalled a protic solvent. The molecules of such solvents can donate an H⁺(proton). Examples of polar protic solvents include, but are not limitedto, water or an alcohol, e.g. methanol, ethanol propanol, isopropanol orbutanol, or a carboxylic acid such as acetic acid or formic acid. Otherpolar solvents are aprotic. Examples of such aprotic polar liquidsinclude, but are not limited to, tetrahydrofuran, pyridine, dioxane,diethyl ether, diisopropylether, ethylene glycol monobutyl ether,pyridine, methyl propyl ketone, methyl isoamyl ketone, methyl isobutylketone, cyclo-hexanone, isobutyl isobutyrate, ethylene glycol diacetate,ethyl acetate, acetonitrile, dimethyl-formamide, N,N-dimethyl acetamide,N-methylpyrrolidone, formamide, and a polar ionic liquid. Examples of apolar ionic liquid include, but are not limited to,1-ethyl-3-methylimidazolium tetrafluoroborate,N-butyl-4-methylpyridinium tetrafluoroborate,1,3-dialkylimidazolium-tetrafluoroborate,1,3-dialkylimidazolium-hexafluoroborate, 1-ethyl-3-methylimidazoliumbis(penta-fluoroethyl)phosphinate, 1-butyl-3-methylimidazoliumtetrakis(3,5-bis(trifluoromethylphenyl)-borate, tetrabutyl-ammoniumbis(trifluoromethyl)imide, ethyl-3-methylimidazoliumtrifluoro-methanesulfonate, 1-butyl-3-methylimidazolium methylsulfate,1-n-butyl-3-methylimidazolium ([bmim]) octylsulfate, and1-n-butyl-3-methylimidazolium tetrafluoroborate.

In some embodiments the first compound, the second compound and thecompound of formula (X) are provided in a coordinating solvent. Acoordinating solvent may for instance include an ether or an amine, suchas an alkylamine or a dialkylamine. In addition the solvent may in suchan embodiment also include non-coordinating components such as an alkaneor an alkene. Illustrative examples of an ether solvent include, but arenot limited to, diethylether, methyl ethyl ether, methyl tert-butylether, dimethoxyethane, THF, dioxane or diphenyl ether.

The reaction of compound (1) and compound (2) yields a compound ofgeneral formula (23)

The moieties R¹ to R⁴ are as defined above.

The reaction of compound (1) and compound (4) yields a compound ofgeneral formula (35)

The moieties R¹ to R⁵ are as defined above.

The reaction of compound (1) and compound (6) yields a compound ofgeneral formula (27)

The moieties R¹ to R⁴ are as defined above.

The reaction between the first and the second compound is allowed toproceed for a period of time sufficient to allow the formation of aproduct of formula (23), of formula (35) or of formula (27),respectively. In some embodiments the occurrence of the respectiveproduct is monitored using a suitable spectrometric and/orchromatographic technique. In some embodiments the reaction is allowedto proceed for a predetermined period of time. Such a predeterminedperiod of time may for instance be based on optimization experimentscarried out in advance. In some embodiments the compound of Formula (1)and the nitro compound of formula (2) are allowed to react for a periodof time selected in the range from about 10 minutes to about 48 hours,such as from about 15 minutes to about 36 hours, from about 15 minutesto about 24 hours, from about 15 minutes to about 16 hours or from about15 minutes to about 12 hours, such as e.g. about 1, about 2, about 3,about 4, about 5, about 6, about 10, about 14 hours or about 18 hours.

As indicated above, the reaction proceeds in an asymmetric manner inhigh enantioselectivities. The stereochemistry of the respective productmay be analysed according to any method known in the art, such as forinstance 2D-NMR based on homo- or heteronuclear J-coupling values(Riccio, R., et al., Pure Appl. Chem. (2003) 75, 2-3, 295-308), electronionization mass spectrometry, polarimetry, circular dichroismspectroscopy (e.g. using the split Cotton-effect based on the Davydovsplitting, see e.g. Allemark, S. G., Nat. Prod. Rep. (2000) 17,145-155), enantioselective chromatography, derivatization in combinationwith standard analytical techniques such as NMR, including any suitable2D-NMR technique, for example based on the nuclear Overhauser effect, aswell as X-ray crystallography or solid state NMR (see e.g. Harper, J.K., et al., J. Org. Chem. (2003) 68, 4609-4614).

Carrying out a reaction of the invention using a chiral compound acyclic product can be obtained in an enantiomerically enriched form, aswell as at least essentially pure enantiomers of the correspondingproduct. The product may be obtained in an enantiomeric excess of atleast 50% ee, at least 60% ee, at least 70% ee, at least 80% ee, atleast 85% ee, at least 87% ee, at least 90% ee, at least 92% ee, atleast 93% ee, at least 94% ee, at least 95% ee, at least 96% ee, atleast 97% ee, at least 98% ee, at least 98.5% ee or at least 99% ee.

The compound of formula (X) may be used in racemic form. The compound offormula (X) may also be used in enantiomeric pure or enantiomericallyenriched form, in particular when carrying out an asymmetric reaction.The compound of general formula (X) may be one of formulas (XA) and (XB)

Without being bound by theory the compound of general formula (X) may beused as a chiral catalyst. In such embodiments the catalyst employed ina process of the invention is a non-racemic chiral compound. Typically,the catalyst is in such embodiments of one of formulas (XA) and (XB).

Where the compound of formula (X) is used in the form of enantiomer (XA)the product of the reaction between the compound of the general formula(1) and the compound of the general formula (2) is at least essentiallya compound of general formula (3)

Where the compound of formula (X) is used in the form of enantiomer (XA)the product of the reaction between the compound of the general formula(4) and the compound of the general formula (2) is at least essentiallya compound of general formula (5)

Where the compound of formula (X) is used in the form of enantiomer (XA)the product of the reaction between the compound of the general formula(6) and the compound of the general formula (2) is at least essentiallya compound of general formula (7)

The hydroxyl group of the compound of formula (23) may be furtherconverted to a derivative such as, but not limited to, an ether, athioether, a selenoether, a silylether, an ester, a thioester, aselenoster, an amide, a carbonate or a carbamate. Thereby the compoundof formula (23) may be converted to a compound of formula (33).

In formula (33) R¹¹ may accordingly be H or a moiety different from H.R¹¹ may be a silyl group as defined above. R¹¹ may also be one of analiphatic group, an alicyclic group, an aromatic group, an arylaliphaticgroup and an arylalicyclic group. A respective aliphatic, alicyclic,aromatic, arylaliphatic or arylcycloaliphatic group may have a mainchain that typically includes 1 to about 30 carbon atoms, such as 2 toabout 30 carbon atoms or 3 to about 30 carbon atoms, including about 1to about 20 carbon atoms, about 2 to about 20 carbon atoms, about 3 toabout 20 carbon atoms, about 1 to about 15 carbon atoms, about 2 toabout 15 carbon atoms, about 1 to about 10 carbon atoms, about 2 toabout 10 carbon atoms or about 1 to about 8 carbon atoms, such as 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbonatoms. The respective main chain of the aliphatic, alicyclic, aromatic,arylaliphatic or arylalicyclic group of R¹¹ may have 0 to about 8heteroatoms, such as 0 to about 7 or 0 to about 6, e.g. 0 to about 5 or0 to about 4, such as 0, 1, 2, 3, 4, 5 or 6 heteroatoms. R¹¹ may also bea carbonate group —O—C(O)—O—R¹⁷ or a carbamoyl group —O—C(O)—N(R¹⁷)—R¹⁸.R¹⁷ and R¹⁸ are independent from one another H or one of an aliphatic,an alicyclic, an aromatic, an arylaliphatic, and an arylalicyclic group.A respective aliphatic, alicyclic, aromatic, arylaliphatic orarylcycloaliphatic group may have a main chain that includes 1 to about30 carbon atoms, such as 2 to about 30 carbon atoms or 3 to about 30carbon atoms, including about 1 to about 20 carbon atoms, about 2 toabout 20 carbon atoms, about 3 to about 20 carbon atoms, about 1 toabout 15 carbon atoms, about 2 to about 15 carbon atoms, about 1 toabout 10 carbon atoms, about 2 to about 10 carbon atoms or about 1 toabout 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19 or 20 carbon atoms. The main chain of thealiphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group mayinclude 0, 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O, S, Se andSi.

In some embodiments R¹¹ in formula (33), as well as R¹¹ in formulas(34), (37) and (24) below, may be a protective group such as an ether, asilyl ether, an ester, a sulfonate, a sulfonate, a sulfinate, acarbonate, a carbamate or a borate ester. Examples of an ether include,but are not limited to, a methoxymethyl ether, an ethoxyethyl ether, a2-hydroxyethyl ether, a methylthiomethyl ether, a t-butyl ether, atriphenylmethyl ether, a t-butoxymethyl ether, a trimethylsilylethylether, a 1-[2-(trimethylsilyl)ethoxy]ethyl ether, a(phenyldimethylsilyl)meth-oxymethyl ether, a benzyl ether, a halobenzoylether, a p-cyanobenzyl ether, a 2-trifluoromethyl-benzyl ether, ap-nitrophenyl ether, a p-phenylbenzyl ether, a trimethylsilylxylylether, a p-(methyl-sulfinyl)benzyl ether, a p-siletanylbenzyl ether, a2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl ether, a benzyloxymethylether, a p-methoxybenzyl ether, a 3,4-dimethoxybenzy ether, a2,6-dimethoxybenzyl ether, a p-nitrobenzyloxymethyl ether, a(4-methoxyphenoxy)methyl ether, a p-nitrobenzyl ether, a cyclohexylether, an allyl ether, a 2-phenylallyl ether, a prenyl ether, a cinnamylether, a propargyl ether, a (benzylthio)ethyl ether, an1-methyl-1-benzyloxyethyl ether, a [3,4-dimethoxybenzyl]oxy)methylether, a tetrahydropyranyl ether, a tetrahydrothiopyranyl ether, amethoxycyclohexyl ether, a1-[(2-chloro-4-methyl)phenyl}-4-methoxypiperidin-4-yl ether, a1-[(2-fluorophenyl}-4-methoxypiperidin-4-yl ether, a 1,4-dioxan-2-ylether, a tetrahydrofuranyl ether, a tetrahydrothiofuranyl ether, a2,2,2-trichloroethyl ether, a 1,1-dianisyl-2,2,2-trichloroethyl ether, a1,1,1,3,3,3-hexafluoro-2-phenylisopropyl ether, apentadienylnitropiperonyl ether, a 2-naphtylmethyl ether, a 2-picolylether, a 1-pyrenylmethyl ether, a 2-quinolinylmethyl ether, a5-dibenzosuberyl ether, a4,4′,4″-tris(4,5-dichlorophtalimidophenyldiphenyl)methyl ether, a 4,4′,4″-tris(levulinoyloxyphenyl)methyl ether, a4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl)-trityl ether, ananthryl ether and a 4,5-bis(ethoxycarbonyl)-[1,3]-dioxolan-2-yl ether.

Examples of a silyl ether include, but are not limited to, atrimethylsilyl ether, a triethylsilyl ether, a triisopropylsilyl ether,a triphenylsilyl ether, a dimethylisopropylsilyl ether, adiethylisopropylsilyl ether, a dimethylthexylsilyl ether, at-butyldimethylsilyl ether, a norbornyl-dimethylsilyl ether, at-butyldiphenylsilyl ether, a tribenzylsilyl ether, a tri-p-xylylsilylether, a diphenylmethylsilyl ether, a di-t-butylmethylsilyl ether, abis(t-butyl)-1-pyernylmethoxysilyl ether, a tris(trimethylsilyl) silylether, a (2-hydroxystyryl)dimethylsilyl ether, a(2-hydroxystyryl)-diisopropylsilyl ether, a t-butylmethoxyphenylsilylether, a t-butoxydiphenylsilyl ether and a1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-ylether. Examples of an ester include, but are not limited to, an acetategroup, a chloroacetate group, a trichloroacetate group, a2,6-dichloro-4-methylphenoxyacetate group, a2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate group, atrifluoroacetate group, a chlorodiphenylacetate group, a2,4-bis(1,1-dimethyl-propyl)phenoxyacetate group, a trichloroacetimidategroup, a benzoate group, a 2-chlorobenzoate group, a p-phenylbenzoategroup, a 2,4,6-trimethylbenzoate group, a 2,5-difluorobenzoate group, ap-nitrobenzoate group, an o-(methoxycarbonyl)benzoate group, abenzoylformate group, a methoxyacetate group, a phenoxyacetate group, aphenylacetate group, a diphenylacetate group, a 3-phenylpropionategroup, a 4-penteneoate group, a 4-oxopentanoate group, a4,4′-(ethylene-dithio)pentanoate group, a5-[3-bis(4-methoxyphenyl)hydroxylmethylphenoxy]levulinate group, apivalonate group, a 1-adamantoate group, a crotonate group, a4-methoxycrotonate group, a picolinate group, a nicotinate group, anisobutyrate group, a monosuccinate group, a Tigloate group and anaphthoate group.

Examples of a sulfonate include, but are not limited to, anallylsulfonate, a methanesulfonate, a benzylsulfonate, a tosylate, a2-[4-nitrophenyl)ethyl]sulfonate and a 2-trifluoromethylsulfonate. Twoillustrative examples of a sulfonate are 4-monomethoxytrityl-sulfonateand an alkyl-2,4-dinitrophenylsulfonate. Examples of a carbonateinclude, but are not limited to, an alkyl methyl carbonate, amethoxymethyl carbonate, an ethyl carbonate, a bromoethyl carbonate, a2-(methylthiomethoxy)ethyl carbonate, a 2,2,2-trichloroethyl carbonate,a 1,1-dimethyl-2,2,2-trichloroethyl carbonate, a 2-(trimethylsilyl)ethylcarbonate, a 2-(dimethyl(2-naphtylmethyl)silyl]ethyl carbonate, a2-(triphenylphosphonio)ethyl carbonate, acis-[4-[[(methoxytrityl)sulfonyl]oxy]tetrahydrofuran-3-yl]oxy carbonate,a 9-fluorenylmethyl carbonate, a vinyl carbonate, an allyl carbonate, anisobutyl carbonate, a t-butyl carbonate, a cinnamyl carbonate, apropargyl carbonate, a phenacyl carbonate, a p-chlorophenyl carbonate, ap-nitrophenyl carbonate, a 4-ethoxy-1-naphthyl carbonate, a6-bromo-7-hydroxycoumarin-4-ylmethyl carbonate, a o-nitrobenzylcarbonate, a p-nitrobenzyl carbonate, a p-methoxybenzyl carbonate, a3,4-dimethoxybenzyl carbonate, an anthraquinon-2-ylmethyl carbonate, adansylethyl carbonate, a 2-(4-nitrophenyl)ethyl carbonate, a2-(2,4-nitrophenyl)ethyl carbonate, a 2-(2-nitrophenyl)propyl carbonate,a 2-(3,4-methylenedioxy-6-nitrophenyl)propyl carbonate, a2-cyano-1-phenylethyl carbonate, a 2-(2-pyridyl)amino-1-phenylethylcarbonate, a 2-[N-methyl-N-(2-pyridyl)amino-1-phenylethyl carbonate, a3′,5′-dimethoxybenzoin carbonate, a methyl dithiocarbonate and anS-benzyl thicarbonate. Three illustrative examples of a carbamate are adimethylthiocarbamate, an N-phenylcarbamate and anN-methyl-N-(o-nitrophenyl) carbamate.

The compound of general formula (3) may accordingly be further convertedto a compound of formula (34)

Likewise, the hydroxyl group of the compound of formula (27) may befurther converted to a derivative such as, but not limited to, an ether,a thioether, a selenoether, a silylether, an ester, a thioester, aselenoster, an amide, a carbonate or a carbamate. Thereby the compoundof formula (23) may be converted to a compound of formula (37).

In formula (37) R¹¹ may accordingly be H or a moiety different from H.R¹¹ may be as defined above (cf. the explanations on formula (33).

The compound of general formula (7) may accordingly be further convertedto a compound of formula (24)

In order that the invention may be readily understood and put intopractical effect, particular embodiments will now be described by way ofthe following non-limiting examples.

Exemplary Embodiments of the Invention General Information

Analytical thin layer chromatography (TLC) was performed using Merck 60F254 precoated silica gel plate (0.2 mm thickness). Subsequent toelution, plates were visualized using UV radiation (254 nm) onSpectroline Model ENF-24061/F 254 nm. Further visualization was possibleby staining with basic solution of potassium permanganate or acidicsolution of ceric molybdate.

Flash chromatography was performed using Merck silica gel 60 withfreshly distilled solvents. Columns were typically packed as slurry andequilibrated with the appropriate solvent system prior to use.

Proton nuclear magnetic resonance spectra (¹H NMR) were recorded onBruker AMX 400 spectrophotometer (CDCl₃ as solvent). Chemical shifts for¹H NMR spectra are reported as δ in units of parts per million (ppm)downfield from SiMe₄ (δ0.0) and relative to the signal of chloroform-d(δ7.2600, singlet). Multiplicities were given as: s (singlet), d(doublet), t (triplet), dd (doublets of doublet) q (quartet) or m(multiplets). The number of protons (n) for a given resonance isindicated by nH. Coupling constants are reported as a J value in Hz.Carbon nuclear magnetic resonance spectra (¹³C NMR) are reported as δ inunits of parts per million (ppm) downfield from SiMe₄ (δ0.0) andrelative to the signal of chloroform-d (δ77.03, triplet).

Enantioselectivities were determined by High performance liquidchromatography (HPLC) analysis employing a Daicel Chirapak AD-H or AS-Hcolumn. Optical rotations were measured in CH₂Cl₂ on a Schmidt+Haenschpolarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL).

High resolution mass spectrometry (HRMS) was recorded on Finnigan MAT95×P spectrometer.

Readily accessible cinchona alkaloid and derivative catalysts, whichwere developed recently in several research groups, have been identifiedas efficient bifunctional organocatalysts in asymmetric Michaelreactions (For developments and applications of cinchona-derivedbifunctional catalysts, see: (a) McCooey, S H, & Connon, S J, Angew.Chem. Int. Ed. (2005) 44, 6367; (b) Ye, J, et al., Chem. Commun. (2005)4481; (c) Vakulya, B, et al., Org. Lett. (2005) 7, 1967; (d) Tillman, A.L, et al., Chem. Commun. (2006) 1191; (e) Mattson, A E, et al., J. Am.Chem. Soc. (2006) 128, 4932. (f) Song, J, et al., Am. Chem. Soc. (2006)128, 6048. (g) McCooey, S H, & Connon, S J, Org. Lett. (2007) 9, 599.(h) Bernardi, L, et al., Tetrahedron (2006) 62, 375; (i) France, S, etal, J. Am. Chem. Soc. (2005) 127, 1206; (j) Taggi, A E, et al., J. Am.Chem. Soc. (2000) 122, 7831) and nitroaldol reactions, also called Henryreactions (Marcelli, T, et al., Angew. Chem. Int. Ed. (2006) 45, 929;Li, H, et al., J. Am. Chem. Soc. (2006) 128, 732). The present inventorsexplored the feasibility of employing thiourea catalyst I (FIG. 2) tocatalyze the tandem Michael-Henry reactions involving a nitroolefin andcarbon nucleophiles 1a containing three carbonyl groups. Surprisingly,the tandem Michael-Henry reaction proceeded smoothly to yield thedesired cyclohexane product in high yield (85%) and goodenantioselectivity (80% ee) and diastereoselectivity (92:8 dr, FIG. 3,entry 1). To improve the results, different conditions wereinvestigated. However, the results did not change significantly when thereaction was carried out in solvent or when the reaction temperature wasdecreased (FIG. 3, entries 2 and 3). Catalysts II-VI (FIG. 2) werescreened at room temperature (23° C.) under neat conditions. V and VIwere identified as excellent candidates to catalyze this tandem reactionwith the highest stereoselectivity (92% ee, 95:5 dr) among all thetested cases, as shown in FIG. 3.

Catalyst VI (for pervious disclosures related to using this type ofcatalyst, see: (a) Xie, J-W, et al., Angew. Chem. Int. Ed. (2007) 46,389; (b) Xie, J-W, et al., Org. Lett. (2007) 9, 413; (c) Barton, G, etal., Org. Lett. (2007) 9, 1403; (d) McCooey, S H, & Connon, S J, Org.Lett. (2007) 9, 599; (e) Zheng, B-L, et al., Org. Biomol. Chem. (2007)5, 2913) was then chosen as catalyst due to the higher yield obtainedand its easy synthesis. Further optimization of the reaction conditionsrevealed that solvents played a very important role in determining theselectivities of the reaction (in toluene or diethyl ether, >99% ee,98:2 dr) (FIG. 3, entries 9-11).

With the optimized reaction conditions at hand, the scope of the tandemMichael-Henry process was expanded by using a variety of nitroolefins indiethyl ether at room temperature. Most of the reactions were found tobe completed within 24 h with good to excellent yields (85%-94%), withexcellent enantioselectivities (97% to >99% ee) anddiastereoselectivities (93:7-98:2 dr). It appeared that the position andthe electronic property of the substituents on aromatic rings have avery limited effect on the stereoselectivities.

Regardless of the types of substituents on the aromatic rings, be itelectron-withdrawing (FIG. 4, entries 9 and 10) or electron-donating(entries 2-4), neutral groups (entry 1) and substrates containing avariety of substitution patterns (para, meta, and ortho) participated inthis reaction efficiently. The reactions proceeded to afford highlyenantioselective adducts. Surprisingly, the presence of the nitro groupon the aromatic ring did not cause the enantiomeric excess to decrease.Without being bound by theory, this may be attributed to the primaryamine group in the catalyst that can selectively capture the two nitrogroups. Notably, only one Michael-Henry adduct was obtained from thereaction of nitrodiene 2k in 97% ee (FIG. 5). Theoretically, both β- andδ-positions of 2k are possibly attacked due to the congruous two doublebonds, showing the great regioselectivity and enantioselectivity of thismethod. Furthermore, the tandem reaction also proceeded smoothly when 1awas replaced by either 1b or 1c, giving excellent stereoselectivities(99% ee) as displayed in FIG. 5.

According to the dual activation model (Mattson, A E, et al., J. Am.Chem. Soc. (2006) 128, 4932), the two substrates involved in thereaction are activated simultaneously by catalyst VI as shown in FIG.15. Nitroolefins are assumed to interact with the primary amine moietyof VI via multiple H-bonds, thus enhancing the electrophilic characterof the reacting carbon center. The carboanion (adjacent to the nitrogroup) generated from the Michael addition then attacks the si-face ofthe carbonyl group to afford Henry products (FIG. 15). Thestereochemistry was established by X-ray crystallographic determinationof 3f (CCDC 670273) and analysis of NMR data of the products.

Typical Procedure for Michael-Henry Reactions Yielding CyclohexaneProducts

To a solution of ethyl 2-acetyl-5-oxohexanoate 1a (0.4 mmol, 1.0 eq) andnitroolefin (0.6 mmol, 1.5 eq) in diethyl ether (0.4 mL) was addedcatalyst VI (Q-NH₂) (0.06 mmol, 0.15 eq) at room temperature (23° C.).The resulting mixture was stirred vigorously. After the reaction wascompleted (monitored by TLC or crude NMR), the product was afforded byflash chromatography over silica gel (EtOAc:Hexane=1:10 to 1:5).

(1R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-phenylcyclohexane carboxylate (3a)

The title compound was prepared according to the typical procedure, asdescribed above in 93% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.39-7.37 (m, 2H), 7.28-7.25 (m, 3H), 5.70 (d,J=12.4 Hz, 1H), 4.26-4.20 (m, 1H), 4.14-4.06 (m, 1H), 4.08 (d, J=12.4Hz, 1H), 2.90 (d, J=2.0 Hz, 1H), 2.56-2.50 (m, 1H), 2.01-1.86 (m, 3H),1.75 (s, 3H), 1.38 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.19, 171.37, 134.62, 130.07, 128.31,128.23, 93.19, 69.77, 64.83, 61.44, 46.46, 34.08, 28.83, 27.81, 27.49,13.75.

HPLC: Chiralpak AS-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=10.4 min, t_(R) (minor)=28.5 min; >99% ee.

[α]_(D) ²⁵=−91.9 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₃O₆N, m/z 349.1521, found 349.1525.

(1R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-3-nitrocyclohexanecarboxylate(3b)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.30 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz,2H), 5.67 (d, J=12.4 Hz, 1H), 4.27-4.21 (m, 1H), 4.14-4.09 (m, 1H), 4.00(d, J=12.8 Hz, 1H), 3.77 (s, 3H), 2.94 (d, J=3.0 Hz, 1H), 2.57-2.50 (m,1H), 2.07-1.83 (m, 3H), 1.76 (s, 3H), 1.37 (s, 3H), 1.20 (t, J=6.8 Hz,3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.49, 171.45, 159.28, 131.20, 126.45,113.67, 93.34, 69.77, 64.91, 61.43, 55.13, 45.94, 34.07, 28.96, 27.77,27.49, 13.81.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (major)=18.7 min, t_(R) (minor)=21.2 min; 98% ee.

[α]_(D) ²⁵=−120.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₉H₂₅O₇N, m/z 379.1626, found 379.1629.

(1R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-p-tolylcyclohexanecarboxylate (3c)

The title compound was prepared according to the typical procedure, asdescribed above in 89% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.25 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz,2H), 5.69 (d, J=12.8 Hz, 1H), 4.28-4.20 (m, 1H), 4.15-4.07 (m, 1H), 4.02(d, J=12.8 Hz, 1H), 2.93 (d, J=2.0 Hz, 1H), 2.57-2.50 (m, 1H), 2.28 (s,3H), 2.00-1.85 (m, 3H), 1.75 (s, 3H), 1.36 (s, 3H), 1.19 (t, J=7.2 Hz,3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.38, 171.41, 137.92, 131.49, 129.91,129.02, 93.29, 69.76, 64.87, 61.41, 46.20, 34.08, 28.93, 27.79, 27.50,21.05, 13.78.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=220nm), t_(R) (major)=13.0 min, t_(R) (minor)=16.3 min; 98% ee.

[α]_(D) ²⁵=−94.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₉H₂₅O₆N, m/z 363.1678, found 363.1676.

(1R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-m-tolylcyclohexanecarboxylate (3d)

The title compound was prepared according to the typical procedure, asdescribed above in 90% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.21-7.13 (m, 3H), 7.04 (d, J=7.2 Hz, 1H),5.70 (d, J=12.4 Hz, 1H), 4.26-4.19 (m, 1H), 4.12-4.08 (m, 1H), 4.04 (d,J=12.8 Hz, 1H), 2.90 (d, J=2.4 Hz, 1H), 2.56-2.49 (m, 1H), 2.30 (s, 3H),2.00-1.88 (m, 3H), 1.75 (s, 3H), 1.36 (s, 3H), 1.19 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.25, 171.39, 137.78, 134.51, 130.89,128.96, 128.15, 126.95, 93.22, 69.75, 64.80, 61.39, 46.35, 34.07, 28.87,27.80, 27.49, 21.40, 13.75.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=254nm), t_(R) (major)=11.0 min, t_(R) (minor)=16.1 min; 99% ee.

[α]_(D) ²⁵=−100.9 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₉H₂₅O₆N, m/z 363.1678, found 363.1679.

(1R,2R,3S,4R)-ethyl-1-acetyl-2-(4-bromophenyl)-4-hydroxy-4-methyl-3-nitrocyclohexane-carboxylate(3e)

The title compound was prepared according to the typical procedure, asdescribed above in 88% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.39 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz,2H), 5.59 (d, J=12.4 Hz, 1H), 4.27-4.22 (m, 1H), 4.12-4.06 (m, 1H), 4.10(d, J=12.4 Hz, 1H), 2.85 (d, J=2.0 Hz, 1H), 2.50-2.44 (m, 1H), 2.00-1.91(m, 3H), 1.83 (s, 3H), 1.36 (s, 3H), 1.19 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.91, 171.26, 133.77, 131.82, 131.42,122.43, 93.07, 69.75, 64.61, 61.61, 45.68, 34.06, 28.74, 27.74, 27.41,13.77.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=220nm), t_(R) (minor)=13.2 min, t_(R) (major)=14.9 min; >99% ee.

[α]_(D) ²⁵=−82.0 (c=0.9, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₂O₆NBr, m/z 429.0605, found 429.0591.

(R,2R,3S,4R)-ethyl-1-acetyl-2-(2-bromophenyl)-4-hydroxy-4-methyl-3-nitrocyclohexane-carboxylate(3f)

The title compound was prepared according to the typical procedure, asdescribed above in 90% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.99 (dd, J=1.2, 8.0 Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.34-7.28 (m, 1H), 7.15-7.11 (m, 1H), 5.95 (d, J=12.4 Hz, 1H),4.64 (d, J=12.4 Hz, 1H), 4.24-4.19 (m, 2H), 2.96 (d, J=2.0 Hz, 1H),2.88-2.82 (m, 1H), 2.03-1.96 (m, 1H), 1.89-1.84 (m, 1H), 1.83 (s, 3H),1.69-1.61 (m, 1H), 1.37 (s, 3H), 1.23 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.07, 171.09, 134.58, 133.57, 130.53,129.82, 127.84, 127.56, 93.28, 69.81, 64.69, 61.68, 44.25, 33.86, 28.90,28.06, 27.43, 13.87.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=16.0 min, t_(R) (major)=20.3 min; 97% ee.

[α]_(D) ²⁵=−134.8 (c=1.1, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₂O₆NBr, m/z 429.0605, found 429.0596.

(1R,2R,3S,4R)-ethyl-1-acetyl-2-(4-chlorophenyl)-4-hydroxy-4-methyl-3-nitrocyclohexane-carboxylate(3g)

The title compound was prepared according to the typical procedure, asdescribed above in 87% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.32 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz,2H), 5.60 (d, J=12.4 Hz, 1H), 4.27-4.21 (m, 1H), 4.13-4.06 (m, 1H), 4.10(d, J=12.8 Hz, 1H), 2.85 (s, 1H), 2.50-2.43 (m, 1H), 2.01-1.90 (m, 3H),1.82 (s, 3H), 1.37 (s, 3H), 1.19 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.93, 171.27, 134.19, 133.23, 131.48,128.47, 93.13, 69.75, 64.66, 61.60, 45.63, 34.06, 28.74, 17.74, 27.42,13.77.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=9.2 min, t_(R) (major)=10.7 min; 97% ee.

[α]_(D) ²⁵=−101.0 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₂O₆NCl, m/z 383.1131, found 383.1134.

(R,2R,3S,4R)-ethyl-1-acetyl-2-(2-chlorophenyl)-4-hydroxy-4-methyl-3-nitrocyclohexane-carboxylate(3h)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.96 (d, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz,1H), 7.29-7.21 (m, 2H), 5.93 (d, J=12.0 Hz, 1H), 4.64 (d, J=12.4 Hz,1H), 4.25-4.17 (m, 2H), 2.91 (d, J=2.4 Hz, 1H), 2.87-2.82 (m, 1H),2.04-1.99 (m, 1H), 1.93-1.86 (m, 1H), 1.75 (s, 3H), 1.68-1.61 (m, 1H),1.38 (s, 3H), 1.23 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.16, 171.09, 136.23, 132.90, 130.48,130.02, 129.52, 127.14, 93.18, 69.82, 64.71, 61.65, 41.47, 33.91, 28.60,28.01, 27.47, 13.87.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=15.0 min, t_(R) (major)=18.5 min; 97% ee.

[α]_(D) ²⁵=−123.5 (c=1.2, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₂O₆NCl, m/z 383.1131, found 383.1137.

(R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-(4-(trifluoromethyl)phenyl)cyclohexanecarboxylate(3i)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.52 (m, 4H), 5.60 (d, J=12.4 Hz, 1H), 4.26(d, J=12.4 Hz, 1H), 4.26-4.21 (m, 1H), 4.08-4.03 (m, 1H), 2.82 (s, 1H),2.49-2.42 (m, 1H), 2.04-1.98 (m, 3H), 1.84 (s, 3H), 1.38 (s, 3H), 1.15(t, J=6.8 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.65, 171.17, 138.95, 130.54, 130.47,125.09 (q, J=3.6 Hz), 122.49, 93.04, 69.76, 64.56, 61.66, 45.68, 34.09,28.50, 27.73, 27.37, 13.66.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=9.2 min, t_(R) (major)=10.7 min; 97% ee.

[α]_(D) ²⁵=−79.6 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₉H₂₂O₆NF₃, m/z 417.1394, found 417.1397.

(R,2R,3S,4R)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-(2-nitrophenyl)cyclohexane-carboxylate(3j)

The title compound was prepared according to the typical procedure, asdescribed above in 94% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.82 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (dd, J=0.8,8.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.42-7.38 (m, 1H), 5.65 (d, J=12.4 Hz,1H), 4.14 (d, J=12.4 Hz, 1H), 4.28-4.20 (m, 1H), 4.07-3.99 (m, 1H), 3.08(d, J=1.6 Hz, 1H), 2.41-2.37 (m, 1H), 2.13-2.09 (m, 2H), 2.02 (s, 3H),1.39 (s, 3H), 1.14 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.11, 171.11, 151.62, 131.82, 129.77,129.57, 128.94, 125.34, 93.23, 69.84, 63.90, 61.77, 38.34, 33.87, 27.88,27.47, 21.19, 13.66.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=25.9 min, t_(R) (major)=37.9 min; 98% ee.

[α′]_(D) ²⁵=−302.9 (c=0.5, CHCl₃).

HRMS (EI) calcd for C₁₈H₂₂O₈N₂, m/z 394.1371, found 394.1377.

(1R,2R,3S,4R,E)-ethyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-styrylcyclohexanecarboxylate (3k)

To a solution of ethyl 2-acetyl-5-oxohexanoate 1a (0.4 mmol, 1.0 eq) andnitroolefin (2k) (0.6 mmol, 1.5 eq) in diethyl ether (0.4 mL) was addedcatalyst VI (0.06 mmol, 0.15 eq) at room temperature. The resultingmixture was stirred vigorously. After 36 hours the reaction wascompleted (monitored by TLC and crude NMR), the product was afforded byflash chromatography over silica gel in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.33-7.24 (m, 6H), 6.51-6.39 (m, 2H), 5.10 (d,J=11.6 Hz, 1H), 4.31 (q, J=7.2 Hz, 1H), 3.51-3.26 (m, 1H), 3.29 ((d,J=2.4 Hz, 1H), 2.53-2.49 (m, 1H), 2.14 (s, 3H), 2.06-1.94 (m, 2H), 1.32(s, 3H), 1.33 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.44, 171.29, 136.36, 136.08, 128.52,128.11, 126.70, 122.76, 93.38, 69.22, 64.67, 61.69, 45.78, 34.37, 28.55,27.38, 26.99, 14.06.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (major)=15.2 min, t_(R) (minor)=39.6 min; 97% ee.

[α]_(D) ²⁵=−35.4 (c=1.2, CHCl₃).

HRMS (EI) calcd for C₂₀H₂₅O₆N, m/z 375.1678, found 375.1675.

(R,2R,3S,4R)-methyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-phenylcyclohexanecarboxylate (3l)

To a solution of Methyl 2-acetyl-5-oxohexanoate 1b (0.4 mmol, 1.0 eq)and nitroolefin (2a) (0.6 mmol, 1.5 eq) in diethyl ether (0.4 mL) wasadded catalyst VI (0.06 mmol, 0.15 eq) at room temperature. Theresulting mixture was stirred vigorously. After 16 hours the reactionwas completed (monitored by TLC and crude NMR), the product was affordedby flash chromatography over silica gel in 85% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.38-7.36 (m, 2H), 7.27-7.24 (m, 3H), 5.67 (d,J=12.4 Hz, 1H), 4.11 (d, J=12.4 Hz, 1H), 3.69 (s, 3H), 2.88 (d, J=2.0Hz, 1H), 2.56-2.48 (m, 1H), 2.00-1.86 (m, 3H), 1.76 (s, 3H), 1.33 (s,3H).

¹³C-NMR (100 MHz, CDCl₃) δ 202.97, 171.86, 134.53, 130.03, 128.32,128.28, 93.21, 69.76, 64.79, 52.13, 46.38, 34.12, 28.70, 27.79, 27.46.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (major)=18.0 min, t_(R) (minor)=31.5 min; 99% ee.

[α]_(D) ²⁵=−101.3 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₁₇H₂₁O₆N, m/z 335.1365, found 335.1369.

(R,2R,3S,4R)-benzyl-1-acetyl-4-hydroxy-4-methyl-3-nitro-2-phenylcyclohexanecarboxylate (3s)

To a solution of benzyl 2-acetyl-5-oxohexanoate 1c (0.4 mmol, 1.0 eq)and nitroolefin (2a) (0.6 mmol, 1.5 eq) in diethyl ether (0.2 mL) wasadded catalyst VI (0.06 mmol, 0.15 eq) at room temperature. Theresulting mixture was stirred vigorously. After 16 hours the reactionwas completed (monitored by TLC and crude NMR), the product was affordedby flash chromatography over silica gel in 93% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.39-7.33 (m, 5H), 7.26-7.19 (m, 5H), 5.70 (d,J=12.4 Hz, 1H), 5.23 (d, J=12.0 Hz, 1H), 5.01 (d, J=12.0 Hz, 1H), 4.10(d, J=12.4 Hz, 1H), 2.90 (s, 1H), 2.57-2.49 (m, 1H), 1.97-1.78 (m, 3H),1.67 (s, 3H), 1.34 (s, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 203.05, 171.15, 134.55, 134.35, 130.05,128.79, 128.70, 128.57, 128.37, 128.27, 93.15, 69.76, 67.33, 64.94,46.48, 33.98, 28.91, 27.80, 27.46.

HPLC: Chiralpak AS-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=11.2 min, t_(R) (minor)=38.7 min; 99% ee.

[α]_(D) ²⁵=−83.8 (c=1.2, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₅O₆N, m/z 411.1677, found 411.1682.

The stereochemistry of the tandem Michael-Henry reaction: Thestereoselectivities of the tandem Michael-Henry reaction was establishedby determination of the X-ray crystal structure of 3f (the depositionnumber: CCDC 670273) together with NMR.

Further, the domino double Michael reaction was investigated. Thereby anorganocatalytic diastereo- and enantioselective cascade double Michaelreaction was developed, in which two C—C bonds and four contiguousstereogenic centers (containing one adjacent quaternary and tertiarystereocenters) were efficiently created in a one-pot operation with anefficient control of stereochemistry. This catalytic methodology servesas a facile approach to synthetically useful, highly functionalizedchiral cyclopentanes (For reviews of the synthesis and bioactivities ofcyclopentanes, see: (a) Biaggio, F C, et al., Curr. Org. Chem. (2005) 9,419; (b) Silva, L F, Tetrahedron (2002) 58, 9137; (c) Lautens, M, etal., Chem. ReV. (1996) 96, 49; (d) Masse, C E, & Panek, J S, Chem. ReV.(1995) 95, 1293).

The design of a catalytic cascade double Michael addition reactionrequired the consideration of several factors. The reactivity of theα,β-unsaturated substrates that participates in the second conjugateaddition reaction must be reactive enough to allow the intramolecularMichael reaction. In the meanwhile, these substrates should be lessreactive than nitroolefins. Recognition of this reactivity profileallows the design of systems capable of undergoing efficient doubleMichael addition sequences. Furthermore, a carbon nucleophile should besufficiently active to only engage in the first Michael additionreaction. To address this concern, we employed easily enolizedacetoacetate ester to replace the α,β-unsaturated ester.

Since the cinchona alkaloid and derivatives thereof (supra) have beenidentified as efficient bifunctional organocatalysts in asymmetricMichael reactions, they were employed for the double Michael additionreaction. After reacting nitrostyrene with diethyl5-acetylhex-2-enedioate 2 (E:Z) 6:1) in the presence of cinchonaalkaloid catalyst II (15 mol %) at room temperature (22° C.) the desiredproduct could be isolated in 81% yield. Surprisingly a singlediastereoisomer was isolated, albeit not enantiomerically pure (FIG. 6,entry 1). In attempts to improve the yield and enantioselectivity,several catalysts and reaction conditions were screened. Catalyst Iproved to be a very efficient catalyst for Michael reaction. Therefore,I was chosen as the most promising catalyst to screen other conditions.However, the results were not improved significantly when the reactionwas carried out in different solvents or at different reactiontemperatures (FIG. 6, entries 2-5). As such, more catalysts werescreened (in FIG. 2, IV-VII) at room temperature. Catalyst VI was foundto be an excellent candidate to catalyze this domino reaction with thehighest stereoselectivity (97% ee, >99:1 dr) among all the casesinvestigated, as shown in the FIG. 6, entry 10. Further optimization ofthe reaction conditions elucidated that solvents played a very importantrole in determining the selectivities of the reaction and yield (diethylether, >99:1 dr, 97% ee, 91% yield).

With optimized reaction conditions established, a series of nitroolefinswere reacted with unsaturated ester substrates to investigate thegenerality of the domino double Michael process by using catalyst VI indiethyl ether. It was observed that most of the reactions are completedwithin 36 h with good to excellent yields (81-92%), excellentenantioselectivities (90-97% ee) and diastereoselectivities (95:5->99:1dr). A majority of the examples (shown in FIG. 7) indicate that theposition and electronic property of the substituents on aromatic ringshave a very limited effect on the stereoselectivities. Regardless of thetypes of substituents on the aromatic rings, be it electron-withdrawing(FIG. 7, entries 6, 7, 13), -donating (entries 2-5), neutral (entry 1,8, 9) groups and substrates containing a variety of substitution (para,meta, and ortho) groups participated in this reaction efficiently. Theheterocyclic thienyl and furanyl groups (FIG. 7, entries 10-12) alsoparticipated in this process, giving good yields andenantioselectivities. Surprisingly, the presence of the nitro group onthe aromatic ring did not cause a decrease in the enantiomeric excess.Without being bound by theory, this may be attributed to the primaryamine group in the catalyst that can selectively capture the two nitrogroups. Interestingly, the ratio (E:Z) 10:1) of 4a had no effect onreactivity and selectivity (FIG. 8A). The domino reaction also proceededsmoothly when 4a was replaced by 4b, giving excellentstereoselectivities (95% ee) as displayed in FIG. 8B. Notably, only onedouble Michael adduct was obtained from the reaction of nitrodiene 2k in95% ee value (FIG. 8C). Theoretically, both 13- and 8-positions of 2kcan possibly be attacked due to the congruous two double bonds. Thisdemonstrates the high regioselectivity and enantioselectivity of thismethod.

Without being bound by theory, according to experimental results and thedual activation model (Okino, T, et al., J. Am. Chem. Soc. (2005) 127,119) the two substrates involved in the reaction are activated bycatalyst VI as shown in FIG. 15. Nitroolefins are assumed to interactwith the primary amine moiety of VI via multiple H-bonds. In this case,both the nitro group and 13-ketoester group interact with multipleH-bonds so that these two groups are on the same side, thus enhancingthe electrophilic character of the reacting carbon center andcontrolling stereochemistry. The carboanion (adjacent to the nitrogroup) generated from the Michael addition then attacks the double bondof α,β-unsaturated esters to afford double Michael products (FIG. 2).

The stereochemistry was established by X-ray crystallographicdetermination of 5g (FIG. 9) and analysis of NMR data of the products.

Typical Procedure for Double-Michael Reactions

To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq)and nitro olefin (0.45 mmol, 1.5 eq) in diethyl ether (0.4 mL) was addedcatalyst VI (Q-NH₂) (0.045 mmol, 0.15 eq) at room temperature (22° C.).The resulting mixture was stirred vigorously for 16-36 hours. After thereaction was completed (monitored by TLC and crude NMR), the product wasafforded by flash chromatography over silica gel (Et₂O:Hexane=1:10 to1:4).

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-phenylcyclopentanecarboxylate(5a)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.31-7.21 (m, 5H), 5.49 (dd, J=5.2, 7.6 Hz,1H), 5.10 (d, J=4.8 Hz, 1H), 4.26-4.14 (m, 2H), 3.80-3.72 (m, 1H),3.68-3.58 (m, 1H), 3.41-3.33 (m, 1H), 2.88 (dd, J=6.8, 12.8 Hz, 1H),2.50 (dd, J=7.2, 16.8 Hz, 1H), 2.40 (dd, J=7.6, 16.8 Hz, 1H), 2.20 (s,3H), 2.01 (dd, J=10.8, 12.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H), 0.76 (t,J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.09, 170.87, 170.29, 137.16, 128.52,128.48, 127.80, 94.26, 71.28, 61.77, 61.05, 51.54, 40.27, 37.74, 34.20,26.98, 14.16, 13.26.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=230nm), t_(R) (major)=6.2 min, t_(R) (minor)=8.9 min; 97% ee.

[α]_(D) ²²=−3.1 (c=1.0, CH₂Cl₂).

HRMS (ESI) calcd for C₂₀H₂₆NO₆+H, m/z 392.1709, found 392.1707.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(4-methoxyphenyl)-3-nitro-cyclopentanecarboxylate(5b)

To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq)and 1-methoxy-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethylether (0.4 mL) was added catalyst VI (Q-NH₂) (0.06 mmol, 0.2 eq) at roomtemperature (22° C.). The resulting mixture was stirred vigorously for24 hours, then the reaction was continued for about 6 hours afterremoval of the solvent. After the reaction was completed (monitored byTLC and crude NMR), the title product was afforded by flashchromatography over silica gel (Et₂O:Hexane=1:10 to 1:3) in 83% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.15 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8, Hz,2H), 5.44 (dd, J=5.6, 7.6 Hz, 1H), 5.02 (d, J=5.2 Hz, 1H), 4.24-4.15 (m,2H), 3.83-3.76 (m, 1H), 3.78 (s, 3H), 3.63-3.57 (m, 1H), 3.51-3.43 (m,1H), 2.86 (dd, J=6.8, 12.8 Hz, 1H), 2.48 (dd, J=7.6, 16.8 Hz, 1H), 2.40(dd, J=7.6, 16.8 Hz, 1H), 2.19 (s, 3H), 2.00 (dd, J=10.8, 12.8 Hz, 1H),1.30 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.36, 170.90, 170.42, 159.14, 129.59,128.96, 113.85, 94.32, 71.02, 61.77, 61.03, 55.31, 50.97, 39.88, 37.72,34.27, 27.06, 14.15, 13.39.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=8.1 min, t_(R) (minor)=12.2 min; 96% ee.

[α]_(D) ²²=−9.0 (c=1.3, CH₂Cl₂).

HRMS (ESI) calcd for C₂₁H₂₇NO₈+H, m/z 422.1815, found 422.1810.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-p-tolylcyclopentane-carboxylate(5c)

The title compound was prepared according to the typical procedure, asdescribed above in 89% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.09 (m, 4H), 5.44 (dd, J=5.2, 7.6 Hz, 1H),5.04 (d, J=5.2 Hz, 1H), 4.24-4.15 (m, 2H), 3.80-3.75 (m, 1H), 3.63-3.57(m, 1H), 3.45-3.41 (m, 1H), 2.87 (dd, J=6.8, 12.8 Hz, 1H), 2.46 (dd,J=7.2, 16.8 Hz, 1H), 2.40 (dd, J=7.6, 17.2 Hz, 1H), 2.30 (s, 3H), 2.19(s, 3H), 2.00 (dd, J=10.8, 12.8 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H), 0.78(t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.25, 170.89, 170.12, 137.52, 133.97,129.12, 128.32, 94.28, 71.13, 61.74, 61.02, 51.29, 40.04, 37.77, 34.26,27.04, 20.99, 14.15, 13.25.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=6.1 min, t_(R) (minor)=8.7 min; 96% ee.

[α]_(D) ²²=−5.7 (c=1.3, CH₂Cl₂).

HRMS (ESI) calcd for C₂₁H₂₇NO₇+H, m/z 406.1866, found 406.1867.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-m-tolylcyclopentane-carboxylate(5d)

The title compound was prepared according to the typical procedure, asdescribed above in 85% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.20-7.17 (m, 1H), 7.10-6.97 (m, 3H), 5.46 (m,1H), 5.05 (d, J=5.2 Hz, 1H), 4.24-4.16 (m, 2H), 3.80-3.72 (m, 1H),3.64-3.58 (m, 1H), 3.45-3.36 (m, 1H), 2.87 (dd, J=6.8, 12.8 Hz, 1H),2.48 (dd, J=6.4, 17.2 Hz, 1H), 2.36 (dd, J=7.6, 16.8 Hz, 1H), 2.32 (s,3H), 2.19 (s, 3H), 2.00 (dd, J=10.8, 12.8 Hz, 1H), 1.30 (t, J=7.2 Hz,3H), 0.77 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.13, 170.88, 170.31, 138.13, 137.06,129.33, 128.48, 128.41, 125.29, 94.36, 71.24, 61.71, 61.02, 51.53,40.21, 37.77, 34.23, 26.99, 21.32, 14.16, 13.23.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=10.6 min, t_(R) (major)=12.0 min; 94% ee.

[α]_(D) ²²=−4.2 (c=1.2, CH₂Cl₂).

HRMS (ESI) calcd for C₂₁H₂₇NO₇+H, m/z 406.1866, found 406.1858.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(4-bromophenyl)-3-nitro-cyclopentanecarboxylate(5e)

The title compound was prepared according to the typical procedure, asdescribed above in 92% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.43 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4 Hz,1H), 5.44 (dd, J=5.6, 7.2 Hz, 1H), 5.04 (d, J=5.2 Hz, 1H), 4.24-4.16 (m,2H), 3.86-3.78 (m, 1H), 3.63-3.57 (m, 1H), 3.53-3.45 (m, 1H), 2.86 (dd,J=6.8, 13.2 Hz, 1H), 2.49 (dd, J=7.2, 16.8 Hz, 1H), 2.39 (dd, J=7.6,17.0 Hz, 1H), 2.19 (s, 3H), 2.00 (dd, J=10.4, 12.4 Hz, 1H), 1.30 (t,J=7.2 Hz, 3H), 0.84 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 199.77, 170.81, 170.12, 136.02, 131.62,130.21, 121.94, 93.72, 70.99, 61.96, 61.10, 50.93, 39.99, 37.70, 34.17,26.96, 14.15, 13.33.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=7.6 min, t_(R) (minor)=11.7 min; 97% ee.

[α]_(D) ²²=−19.0 (c=0.8, CH₂Cl₂).

HRMS (ESI) calcd for C₂₀H₂₄BrNO₇+H, m/z 470.0814, found 470.0808.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(4-chlorophenyl)-3-nitro-cyclopentanecarboxylate(5g)

The title compound was prepared according to the typical procedure, asdescribed above in 88% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.28 (d, J=6.8 Hz, 1H), 7.16 (dd, J=2.0, 7.8Hz, 1H), 5.44 (dd, J=5.6, 7.6 Hz, 1H), 5.05 (d, J=5.2 Hz, 1H), 4.24-4.16(m, 2H), 3.86-3.78 (m, 1H), 3.64-3.57 (m, 1H), 3.52-3.44 (m, 1H), 2.86(dd, J=6.8, 12.8 Hz, 1H), 2.48 (dd, J=7.4, 17.0 Hz, 1H), 2.39 (dd,J=7.6, 17.0 Hz, 1H), 2.19 (s, 3H), 2.00 (dd, J=10.4, 12.4 Hz, 1H), 1.30(t, J=7.2 Hz, 3H), 0.84 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.03, 170.81, 170.14, 135.49, 133.82,129.88, 128.64, 93.79, 71.02, 61.92, 61.09, 50.86, 39.97, 37.70, 34.17,26.97, 14.15, 13.33.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=254nm), t_(R) (major)=7.1 min, t_(R) (minor)=11.1 min; 96% ee.

[α]_(D) ²²=−11.4 (c=1.0, CH₂Cl₂).

HRMS (ESI) calcd for C₂₀H₂₄ClNO₇+H, m/z 426.1320, found 426.1322.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(2-methoxyphenyl)-3-nitro-cyclopentanecarboxylate(5l)

To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq)and 1-meth-oxy-2-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethylether (0.4 mL) was added catalyst VI (Q-NH₂) (0.06 mmol, 0.2 eq) at roomtemperature (22° C.). The resulting mixture was stirred vigorously for24 hours, then the reaction was continued for about 6 hours afterremoval of the solvent. After the reaction was completed (monitored byTLC and crude NMR), the title product was afforded by flashchromatography over silica gel (Et₂O:Hexane=1:10 to 1:3) in 81% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.30-7.21 (m, 2H), 6.90-6.89 (m, 1H), 6.78 (d,J=8.0 Hz, 1H), 5.55 (dd, J=4.0, 7.2 Hz, 1H), 5.13 (d, J=4.0 Hz, 1H),4.21-4.13 (m, 2H), 3.90-3.84 (m, 1H), 3.77 (s, 3H), 3.65-3.59 (m, 1H),3.53-3.45 (m, 1H), 2.89 (dd, J=6.4, 12.4 Hz, 1H), 2.48 (dd, J=6.4, 17.2Hz, 1H), 2.34 (dd, J=8.4, 16.8 Hz, 1H), 2.14 (s, 3H), 1.95 (m, 1H), 1.28(t, J=7.2 Hz, 3H), 0.78 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.09, 171.03, 170.20, 157.31, 132.03,129.12, 125.88, 120.85, 110.10, 94.46, 70.76, 61.39, 60.87, 54.90,50.54, 39.78, 37.88, 34.10, 26.50, 14.19, 13.23.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=210nm), t_(R) (minor)=12.4 min, t_(R) (major)=14.6 min; 95% ee.

[α]_(D) ²²=−5.5 (c=1.0, CH₂Cl₂).

HRMS (ESI) calcd for C₂₁H₂₇NO₈+H, m/z 422.1815, found 422.1823.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(naphthalen-3-yl)-3-nitro-cyclopentanecarboxylate(5m)

The title compound was prepared according to the typical procedure, asdescribed above in 84% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.82-7.76 (m, 3H), 7.69 (s, 1H), 7.49-7.47 (m,2H), 7.34 (d, J=8.4 Hz, 1H), 5.64-5.61 (m, 1H), 5.27 (d, J=5.2 Hz, 1H),4.26-4.18 (m, 2H), 3.75-3.63 (m, 2H), 3.26-3.18 (m, 1H), 2.93 (dd,J=6.8, 12.8 Hz, 1H), 2.53 (dd, J=7.6, 16.8 Hz, 1H), 2.45 (dd, J=7.6,16.8 Hz, 1H), 2.21 (s, 3H), 2.45 (dd, J=10.8, 12.8 Hz, 1H), 1.32 (t,J=7.2 Hz, 3H), 0.52 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.22, 170.91, 170.32, 128.17, 127.89,127.48, 127.43, 126.40, 126.28, 126.26, 94.23, 71/30, 61.74, 61.08,51.71, 40.19, 37.86, 34.29, 27.02, 14.18, 13.03.

HPLC: Chiralpak AD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=254nm), t_(R) (minor)=20.5 min, t_(R) (major)=33.5 min; 95% ee.

[α]_(D) ²²=−31.9 (c=0.6, CH₂Cl₂).

HRMS (ESI) calcd for C₂₄H₂₇NO₇+H, m/z 442.1866, found 442.1861.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(naphthalen-1-yl)-3-nitro-cyclopentanecarboxylate(5n)

The title compound was prepared according to the typical procedure, asdescribed above in 87% yield.

¹H-NMR (400 MHz, CDCl₃) δ 8.58 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.4 Hz,1H), 7.77 (d, J=8.4 Hz, 1H), 7.62-7.59 (m, 1H), 7.52-7.49 (m, 1H),7.44-7.40 (m, 1H), 7.23 (d, J=7.2 Hz, 1H), 6.03 (d, J=2.4 Hz, 1H),5.60-5.58 (m, 1H), 4.30-4.17 (m, 2H), 3.76-3.68 (m, 1H), 3.51-3.45 (m,1H), 3.01 (dd, J=6.8, 12.8 Hz, 1H), 2.88-2.83 (m, 1H), 2.62 (dd, J=6.4,17.2 Hz, 1H), 2.43 (dd, J=8.4, 17.2 Hz, 1H), 2.19 (s, 3H), 1.16-2.10 (m,1H), 1.32 (t, J=7.2 Hz, 3H), 0.19 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 199.62, 170.91, 170.19, 135.23, 133.55,132.51, 128.57, 126.75, 126.04, 124.99, 124.75, 124.57, 96.98, 72.47,61.48, 61.11, 46.43, 37.98, 33.91, 26.81, 14.19, 12.51.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=7.7 min, t_(R) (minor)=10.2 min; 95% ee.

[α]_(D) ²²=−29.0 (c=1.0, CH₂Cl₂).

HRMS (ESI) calcd for C₂₄H₂₇NO₇+H, m/z 442.1866, found 442.1861.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(furan-3-yl)3-nitro-cyclopentanecarboxylate(5o)

The title compound was prepared according to the typical procedure, asdescribed above in 86% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.36-7.34 (m, 2H), 6.28 (s, 1H), 5.34-5.31 (m,1H), 4.82 (d, J=6.8 Hz, 1H), 4.22-4.14 (m, 2H), 4.03-3.95 (m, 1H),3.88-3.81 (m, 1H), 3.58-3.52 (m, 1H), 2.83 (dd, J=7.2, 13.2 Hz, 1H),2.41 (d, J=7.6 Hz, 1H), 2.21 (s, 3H), 1.96 (dd, J=10.4, 12.8 Hz, 1H),1.28 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.61, 170.86, 170.57, 143.15, 140.79,120.66, 109.98, 93.37, 69.47, 61.91, 61.04, 43.71, 38.29, 37.85, 34.55,27.21, 14.14, 13.48.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=254nm), t_(R) (minor)=17.9 min, t_(R) (major)=19.0 min; 94% ee.

[α]_(D) ²²=5.7 (c=1.2, CH₂Cl₂).

HRMS (ESI) calcd for C₁₈H₂₃NO₈+H, m/z 382.1502, found 382.1499.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-2-(furan-2-yl)-3-nitro-cyclopentanecarboxylate(5p)

The title compound was prepared according to the typical procedure, asdescribed above in 87% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.31-7.28 (m, 1H), 6.31-6.26 (m, 2H), 5.45(dd, J=5.6, 7.6 Hz, 1H), 5.09 (d, J=5.6 Hz, 1H), 4.22-4.15 (m, 2H),4.04-3.99 (m, 1H), 3.80-3.75 (m, 1H), 3.60-3.53 (m, 1H), 2.88 (dd,J=6.8, 13.2 Hz, 1H), 2.41 (d, J=7.6 Hz, 1H), 2.20 (s, 3H), 1.96-1.90 (m,1H), 1.28 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 199.80, 170.76, 169.98, 149.81, 142.32,110.73, 108.96, 92.07, 69.40, 62.32, 61.03, 46.32, 38.99, 37.50, 34.29,26.73, 14.14, 13.60.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=7.2 min, t_(R) (minor)=11.1 min; 94% ee.

[α]_(D) ²²=−6.3 (c=1.1, CH₂Cl₂).

HRMS (ESI) calcd for C₁₈H₂₃NO₈+Na, m/z 404.1321, found 404.1326.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-(thiophen-2-yl)cyclopentanecarboxylate(5q)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.21-7.20 (m, 1H), 6.93-6.92 (m, 2H),5.52-4.48 (m, 1H), 5.21 (d, J=7.2 Hz, 1H), 4.226-4.14 (m, 2H), 3.96-3.89(m, 1H), 3.75-3.68 (m, 1H), 3.66-3.57 (m, 1H), 2.89 (dd, J=7.2, 12.8 Hz,1H), 2.41 (d, J=7.6 Hz, 1H), 2.21 (s, 3H), 1.96 (dd, J=10.0, 13.2 Hz,1H), 1.29 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.36, 170.76, 170.21, 138.64, 126.82,126.27, 125.36, 94.23, 70.46, 62.10, 61.07, 47.35, 38.31, 37.70, 34.55,27.14, 14.15, 13.48.

HPLC: Chiralpak AS-H (hexane/i—PrOH=95/5, flow rate 1 mL/min, λ=210 nm),t_(R) (minor)=25.0 min, t_(R) (major)=28.1 min; 94% ee.

[α]_(D) ²²=−4.3 (c=1.2, CH₂Cl₂).

HRMS (ESI) calcd for C₁₈H₂₃NO₇S+Na, m/z 420.1093, found 420.1100.

(1R,2R,3R,4S)-ethyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-(4-nitrophenyl)cyclopentanecarboxylate(5r)

To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq)and 1-nitro-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethylether (0.4 mL) was added catalyst VI (Q-NH₂) (0.06 mmol, 0.2 eq) at roomtemperature (22° C.). The resulting mixture was stirred vigorously for24 hours, then the reaction was continued for about 6 hours afterremoval of the solvent. After the reaction was completed (monitored byTLC and crude NMR), the title product was afforded by flashchromatography over silica gel (Et₂O:Hexane=1:10 to 1:3) in 81% yield.

¹H-NMR (400 MHz, CDCl₃) δ 8.17 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.8 Hz,1H), 5.52-5.49 (m, 1H), 5.19 (d, J=5.6 Hz, 1H), 4.25-4.16 (m, 2H),3.86-3.80 (m, 1H), 3.69-3.62 (m, 1H), 3.49-3.43 (m, 1H), 2.89 (dd,J=6.8, 13.2 Hz, 1H), 2.51 (dd, J=7.2, 17.2 Hz, 1H), 2.40 (dd, J=7.6,17.2 Hz, 1H), 2.22 (s, 3H), 2.02 (dd, J=10.8, 12.8 Hz, 1H), 1.30 (t,J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 199.79, 170.73, 169.82, 147.41, 144.35,129.64, 123.60, 93.20, 71.10, 62.07, 61.21, 51.02, 40.01, 37.73, 34.09,26.91, 14.15, 13.42.

HPLC: Chiralpak AS-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=20.9 min, t_(R) (minor)=25.4 min; 97% ee.

[α]_(D) ²²=−9.7 (c=1.0, CH₂Cl₂).

(1R,2R,3R,4S)-benzyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-phenylcyclopentanecarboxylate(5s)

To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate 4b (0.3 mmol,1.0 eq) and 1-((E)-2-nitrovinyl)benzene (0.45 mmol, 1.5 eq) indiethylether (0.4 mL) was added catalyst VI (Q-NH₂) (0.045 mmol, 0.15eq) at room temperature (22° C.). The resulting mixture was stirredvigorously for 16 hours, then the reaction was continued for about 6hours after removal of the solvent. After the reaction was completed(monitored by TLC and crude NMR), the title product was afforded byflash chromatography over silica gel (Ethyl acetate:Hexane=1:10 to 1:4)in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.54-7.14 (m, 8H), 6.96-6.94 (m, 2H), 5.51(dd, J=5.2, 7.2 Hz, 1H), 5.11 (d, J=5.2 Hz, 1H), 4.83 (d, J=12.0 Hz,1H), 4.25-4.16 (m, 2H), 4.10 (d, J=12.0 Hz, 1H), 3.69-3.63 (m, 1H), 2.89(dd, J=6.8, 13.2 Hz, 1H), 2.49 (dd, J=7.6, 16.8 Hz, 1H), 2.40 (dd,J=7.6, 16.8 Hz, 1H), 2.11 (s, 3H), 2.02 (dd, J=10.8, 12.8 Hz, 1H), 1.30(t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 199.84, 170.86, 170.18, 137.04, 134.09,128.63, 128.49, 128.45, 128.28, 127.91, 94.23, 71.41, 67.57, 61.07,51.69, 40.20, 37.81, 34.22, 27.07, 14.17.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=220nm), t_(R) (major)=7.7 min, t_(R) (minor)=11.5 min; 97% ee.

[α]_(D) ²²=−5.0 (c=0.9, CH₂Cl₂).

HRMS (ESI) calcd for C₂₅H₂₇NO₇+H, m/z 454.1866, found 454.1861.

(1R,2R,3R,4S)-benzyl4-((ethoxycarbonyl)methyl)-1-acetyl-3-nitro-2-styrylcyclopentanecarboxylate(5t)

To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate (4b, 0.3 mmol,1.0 eq) and 1-((1E,3E)-4-nitrobuta-1,3-dienyl)benzene (0.6 mmol, 2.0 eq)in diethyl ether (0.4 mL) was added catalyst VI (Q-NH₂) (0.03 mmol, 0.2eq) at room temperature (22° C.). The resulting mixture was stirredvigorously for 24 hours, and then the reaction was continued for about 6hours after removal of the solvent. After the reaction was completed(monitored by TLC and crude NMR), the title product was afforded byflash chromatography over silica gel (Et₂O:Hexane=1:10 to 1:4) in 83%yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.32-7.22 (m, 10H), 6.55 (d, J=16.0, 1H), 6.05(dd, J=8.8, 16.0 Hz, 1H), 5.21-5.17 (m, 1H), 5.18 (d, J=12.0 Hz, 1H),5.05 (d, J=12.0 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 4.26-4.13 (m, 3H),3.45-3.35 (m, 1H), 2.72 (dd, J=7.2, 13.2 Hz, 1H), 2.43-2.40 (m, 2H),2.18 (s, 3H), 2.07 (dd, J=10.8, 13.2 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.66, 170.89, 170.50, 135.91, 135.07,134.36, 128.75, 128.73, 128.62, 128.60, 128.13, 126.55, 123.69, 92.81,69.04, 67.85, 61.03, 51.55, 38.04, 37.63, 34.59, 27.64, 14.15.

HPLC: Chiralpak AD-H (hexane/i—PrOH=90/10, flow rate 1 mL/min, λ=254nm), t_(R) (major)=20.7 min, t_(R) (minor)=22.8 min; 95% ee.

[α]_(D) ²²=−5.3 (c=1.0, CH₂Cl₂).

HRMS (ESI) calcd for C₂₇H₂₉NO₇+H, m/z 480.2022, found 480.2017.

As indicated above cinchona alkaloid and derivatives have beenidentified as efficient bifunctional organocatalysts in asymmetricMichael reactions, Henry reactions (nitroaldol reactions), and tandemMichael-Henry reactions (cf. also FIG. 10). Therefore the feasibility ofthe use of diamine catalyst VI was explored in the hope to be able toallow catalysis of tandem Michael-Henry reactions involving anitroolefin and a rationally designed carbon nucleophile 6a to formchiral cyclopentanes FIG. 10, n=0). However, the enantioselectivity ofthe desired product was only 67% ee (FIG. 11, entry 1). Despite changingthe reaction conditions such as catalysts, solvents, and temperature,the highest enantiomeric excess obtained was 82% (FIG. 11, entries 1-4).The investigation of various substrates demonstrated that the dominoMichael-Henry reaction proceeded smoothly to afford the desiredcyclopentane ring products in high yields (92-95%, FIG. 11, entries 5,7-9) with the exception of the less reactive substrate 6c (FIG. 11,entry 6). Surprisingly, only one diastereomer was obtained in all of thecases investigated. Nevertheless, varied enantioselectivities wereobserved with different substituents on 6. For example, higherenantiomeric excesses (75% ee) were observed when 6a was substitutedwith 6d or 6e.

Despite many attempts, the best result achieved was only 83% ee withcatalyst I. Therefore, it seemed essential to change the organocatalystsfor much higher enantioselectivity. To our delight, the product wasobtained in 93% yield with 90% ee (FIG. 11, entry 13) when catalyst VIwas used. When catalyst IV was used, the lower enantiomeric excessindicated that the OMe group on the catalyst was critical forstereoselectivity (FIG. 11, entry 12). Although the reaction time wasprolonged to 36 h, higher ee (95% ee) was afforded when the reactiontemperature was lowered to 4° C. (FIG. 11, entry 15). The dominoMichael-Henry reaction indeed proceeded smoothly to yield the desiredcyclopentane ring product in excellent yield (95%) and goodenantioselectivity (75% ee). With the optimized reaction conditions, thegenerality of the domino Michael-Henry process was investigated by usinga variety of nitroalkenes. It was observed that all of the reactionswere completed within 72 h, giving adducts in excellent yields (90-95%)and with complete diastereoselectivities and excellentenantioselectivities (88-96% ee). It appeared that the position and theelectronic property of the substituents for aromatic rings had a verylimited influence on the stereoselectivities of the reactions (FIG. 12,entries 2-7). Electron-withdrawing (entries 6, 7 and 11, 12),electron-donating (entries 2-5), and neutral (entries 1 and 10) groups,as well as substrates containing a variety of substitution patterns(para, meta and ortho), participated in this reaction efficiently. Amongaromatic groups also heteroaromatic groups such as furyl and thienylcould be successfully employed to afford the respective cyclopentanederivatives with excellent enantioselectivity (entries 8 and 9).Surprisingly, the presence of the nitro group on the aromatic ring(entry 11) did not decrease the enantiomeric excess. Without being boundby theory this demonstrates that the primary amine group in the catalystis able to capture one of the two nitro groups selectively. Furthermore,the domino reaction also proceeded smoothly when 6a was replaced witheither 6b or 6c, as displayed in FIG. 13.

The dual activation model was proposed (Okino et al., 2005, supra) wherethe two substrates involved in the reaction are activated simultaneouslyby catalyst VI as shown in the FIG. 17. Nitroolefins have been assumedto interact with the primary amine moiety of VI via multiple H-bonds,thus enhancing the electrophilic character of the reacting carboncenter. However, the enolic form of 6 is assumed to interact with thetertiary amine group and a subsequent deprotonation results in a highlynucleophilic enolate species. The carbonanion adjacent to the nitrogroup then attacks the carbonyl group to afford Henry products. Theabsolute configuration of 7f was determined by X-ray crystallography(FIG. 14, see the data below). The stereochemistry of this dominoreaction was then established by analysis of the X-ray crystalstructures together with analysis of the NMR data.

Typical Procedure for the Michael-Henry Reactions Yielding CyclopentaneProducts

To a solution of ethyl 2-acetyl-4-oxo-4-phenylbutanoate 6d (1.0 mmol, 2eq) and nitroolefins (0.5 mmol, 1 eq) in toluene (0.5 mL) was addedcatalyst VI (Q-NH₂) (0.05 mmol, 0.1 eq) at 4° C. The resulting mixturewas stirred vigorously at 4° C. After the reaction was complete(monitored by TLC), the products were afforded by flash columnchromatography over silica gel (EtOAc:Hexane=1:10 to 1:6).

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-2,4-diphenylcyclopentanecarboxylate(7a)

The title compound was prepared according to the typical procedure, asdescribed above in 93% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.64 (d, J=7.6, 2H), 7.47-7.28 (m, 8H), 5.80(d, J=12.4 Hz, 1H), 5.43 (d, J=12.4 Hz, 1H), 3.82-3.76 (m, 2H),3.50-3.42 (m, 1H), 3.27 (d, J=14.4 Hz, 1H), 2.57 (d, J=14.8 Hz, 1H),2.26 (s, 3H), 0.76 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.38, 170.28, 139.67, 134.29, 128.88,128.75, 128.59, 128.52, 128.23, 124.90, 93.31, 81.01, 67.82, 62.23,49.63, 46.44, 26.88, 13.26.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=6.6 min, t_(R) (minor)=10.7 min; 95% ee.

[α]_(D) ²⁵=23.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₂H₂₃NO₆, m/z 397.1520, found 397.1524.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-2-(4-methoxyphenyl)-3-nitro-4-phenylcyclopentanecarboxylate (7b)

The title compound was prepared according to the typical procedure, asdescribed above in 93% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.63 (d, J=7.6, 2H), 7.48-7.28 (m, 8H), 5.74(d, J=12.8 Hz, 1H), 5.36 (d, J=12.8 Hz, 1H), 3.86-3.80 (m, 2H), 3.79 (s,3H), 3.56-3.51 (m, 1H), 3.25 (dd, J=7.2, 14.4 Hz, 1H), 2.56 (d, J=14.4Hz, 1H), 2.27 (s, 3H), 0.83 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.55, 170.44, 159.49, 139.73, 129.90,128.86, 128.57, 126.03, 124.89, 113.88, 93.46, 88.87, 67.68, 62.22,55.31, 49.17, 46.39, 26.95, 13.39.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=10.8 min, t_(R) (minor)=20.7 min; 92% ee.

[α]_(D) ²⁵=23.3 (c=1.2, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₅NO₇, m/z 427.1626, found 427.1629.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-4-phenyl-2-p-tolylcyclopentanecarboxylate (7c)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.61 (d, J=7.6, 2H), 7.45-7.34 (m, 3H),7.29-7.27 (m, 2H), 7.11 (d, J=8.0 Hz, 2H), 5.75 (d, J=12.4 Hz, 1H), 5.36(d, J=12.4 Hz, 1H), 3.83-3.75 (m, 2H), 3.53-3.45 (m, 1H), 3.24 (dd,J=2.0, 14.4 Hz, 1H), 2.54 (d, J=14.8 Hz, 1H), 2.30 (s, 3H), 2.24 (s,3H), 0.77 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.49, 170.35, 139.74, 137.98, 131.10,129.16, 128.86, 128.60, 128.56, 124.90, 93.42, 80.95, 67.76, 62.20,49.42, 46.43, 26.93, 21.04, 13.24.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=6.4 min, t_(R) (minor)=9.4 min; 95% ee.

[α]_(D) ²⁵=12.1 (c=1.5, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₅NO₆, m/z 411.1678, found 411.1682.

(1R,2R,3S,4S)-ethyl-1-acetyl-2-(4-bromophenyl)-4-hydroxy-3-nitro-4-phenylcyclopentanecarboxylate (7e)

The title compound was prepared according to the typical procedure, asdescribed above in 94% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.61 (d, J=7.6, 2H), 7.46-7.42 (m, 4H),7.38-7.37 (m, 1H), 7.30-7.27 (m, 2H), 5.72 (d, J=12.4 Hz, 1H), 5.37 (d,J=12.4 Hz, 1H), 3.87-3.79 (m, 1H), 3.76 (d, J=2.4 Hz, 1H), 3.56-3.51 (m,1H), 3.22 (dd, J=2.0, 14.4 Hz, 1H), 2.53 (d, J=14.8 Hz, 1H), 2.23 (s,3H), 0.82 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.28, 170.23, 139.51, 133.35, 131.64,130.50, 128.92, 128.68, 124.86, 122.35, 92.85, 80.98, 67.55, 62.42,49.02, 46.46, 26.87, 13.33.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=7.1 min, t_(R) (minor)=11.6 min; 91% ee.

[α]_(D) ²⁵=8.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₂H₂₂BrNO₆, m/z 475.0626, found 475.0629.

(1R,2R,3S,4S)-ethyl-1-acetyl-2-(4-chlorophenyl)-4-hydroxy-3-nitro-4-phenylcyclopentanecarboxylate (7g)

The title compound was prepared according to the typical procedure, asdescribed above in 95% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.62 (d, J=7.6, 2H), 7.46-7.42 (m, 2H),7.38-7.35 (m, 3H), 7.30-7.26 (m, 2H), 5.73 (d, J=12.4 Hz, 1H), 5.38 (d,J=12.4 Hz, 1H), 3.87-3.79 (m, 1H), 3.75 (d, J=3.2 Hz, 1H), 3.57-3.49 (m,1H), 3.23 (dd, J=2.0, 14.4 Hz, 1H) 2.53 (d, J=14.8 Hz, 1H), 2.23 (s,3H), 0.82 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.29, 170.24, 139.51, 134.22, 132.80,130.18, 128.92, 128.67, 124.86, 92.93, 80.98, 67.59, 62.40, 48.98,46.45, 26.87, 13.33.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=7.2 min, t_(R) (minor)=11.2 min; 95% ee.

[α]_(D) ²⁵=10.4 (c=1.8, CHCl₃).

HRMS (EI) calcd for C₂₂H₂₂ClNO₆, m/z 431.1132, found 431.1135.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-4-phenyl-2-(thiophen-2-yl)cyclopentanecarboxylate (7q)

The title compound was prepared according to the typical procedure, asdescribed above in 93% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.63 (d, J=3.6, 2H), 7.48-7.36 (m, 3H), 7.26(d, J=4.8 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.96 (t, J=4.4 Hz, 1H), 5.74(d, J=12.4 Hz, 1H), (m, 2H), 5.60 (d, J=12.4 Hz, 1H), 3.95-3.91 (m, 1H),3.73-3.68 (m, 2H), 3.26 (dd, J=2.0, 14.8 Hz, 1H), 2.57 (d, J=14.8 Hz,1H), 2.27 (s, 3H), 0.93 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.39, 170.54, 139.51, 136.68, 128.89,128.65, 126.78, 126.48, 125.98, 124.91, 94.42, 80.91, 67.35, 62.54,46.48, 45.61, 26.91, 13.44.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=8.0 min, t_(R) (minor)=12.6 min; 93% ee.

[α]_(D) ²⁵=21.6 (c=1.8, CHCl₃).

HRMS (EI) calcd for C₂₀H₂₁NO₆S, m/z 403.1086, found 403.1088.

(1R,2R,3S,4S)-ethyl-1-acetyl-2-(furan-2-yl)-4-hydroxy-3-nitro-4-phenylcyclopentanecarboxylate ('7p)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.61 (d, J=8.0, 2H), 7.47-7.39 (m, 4H),6.38-6.35 (m, 2H), 5.74 (d, J=11.6 Hz, 1H), 5.41 (d, J=12.0 Hz, 1H),4.07-4.01 (m, 1H), 3.86-3.80 (m, 1H), 3.66 (s, 1H), 3.25 (d, J=14.8 Hz,1H), 2.58 (d, J=14.8 Hz, 1H), 2.29 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.15, 169.93, 148.62, 142.79, 139.58,128.85, 128.57, 124.88, 110.84, 109.99, 92.67, 80.85, 66.18, 62.72,46.29, 44.31, 26.51, 13.62.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=7.0 min, t_(R) (minor)=10.4 min; 92% ee.

[α]_(D) ²⁵=26.0 (c=1.5, CHCl₃).

HRMS (EI) calcd for C₂₀H₂₁NO₇, m/z 387.1314, found 387.1318.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-4-phenyl-2-o-tolylcyclopentanecarboxylate(7t)

The title compound was prepared according to the typical procedure, asdescribed above in 90% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.60 (d, J=7.6, 2H), 7.48-7.39 (m, 3H),7.19-7.18 (m, 4H), 5.78 (d, J=10.4 Hz, 1H), 5.61 (d, J=10.8 Hz, 1H),3.78-3.72 (m, 1H), 3.65 (s, 1H), 3.43-3.37 (m, 2H), 2.65 (d, J=15.2 Hz,1H), 2.56 (s, 3H), 2.27 (s, 3H), 0.73 (t, J=6.8 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.61, 169.26, 139.72, 139.02, 135.20,130.86, 128.86, 128.52, 127.93, 126.61, 126.13, 124.82, 97.39, 81.30,69.59, 62.14, 46.58, 44.86, 26.32, 20.20, 13.14.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=5.6 min, t_(R) (minor)=7.2 min; 90% ee.

[α]_(D) ²⁵=18.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₅NO₆, m/z 411.1678, found 411.1679.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-2-(3-methoxyphenyl)-3-nitro-4-phenylcyclopentanecarboxylate (7w)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.60 (d, J=8.4, 1H), 7.45-7.35 (m, 3H),7.65-7.63 (m, 3H), 7.24-7.20 (m, 2H), 6.96-6.95 (m, 2H), 6.81 (dd,J=1.6, 8.4 Hz, 1H), 5.74 (d, J=12.4 Hz, 1H), 5.37 (d, J=12.4 Hz, 1H),3.85-3.76 (m, 3H), 3.74 (d, J=2.0 Hz, 1H), 3.56-3.48 (m, 1H), 3.25 (dd,J=2.0, 14.4 Hz, 1H), 2.54 (d, J=14.4 Hz, 1H), 2.24 (s, 3H), 0.79 (t,J=7.2 Hz, 3 H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.36, 159.65, 139.65, 135.84, 129.49,128.87, 128.59, 124.89, 120.53, 114.72, 113.90, 93.43, 81.00, 67.73,62.25, 55.32, 49.62, 46.48, 26.86, 13.30.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=7.6 min, t_(R) (minor)=11.6 min; 92% ee.

[α]_(D) ²⁵=28.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₅NO₇, m/z 427.1626, found 427.1628.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-2-(naphthalen-1-yl)-3-nitro-4-phenylcyclopentanecarboxylate (7n)

The title compound was prepared according to the typical procedure, asdescribed above in 91% yield.

¹H-NMR (400 MHz, CDCl₃) δ 8.73 (d, J=8.4, 1H), 7.84-7.79 (m, 2H),7.65-7.63 (m, 3H), 7.53-7.37 (m, 6H), 6.42 (d, J=10.8 Hz, 1H), 5.85 (d,J=10.8 Hz, 1H), 3.82 (d, J=2.4 Hz, 1H), 3.55-3.44 (m, 2H), 3.07-3.022.66 (d, J=14.8 Hz, 1H), 2.26 (s, 3H), 0.21 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.86, 169.30, 139.62, 133.83, 132.95,128.98, 128.91, 128.62, 128.42, 126.89, 126.16, 124.88, 124.74, 124.35,96.86, 81.38, 69.59, 61.91, 46.41, 43.93, 26.54, 12.60.

HPLC: Chiralcel OD-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=6.9 min, t_(R) (minor)=8.7 min; 96% ee.

[α]_(D) ²⁵=22.1 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₆H₂₅NO₆, m/z 447.1677, found 447.1678.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-2-(4-nitrophenyl)-4-phenylcyclopentanecarboxylate (7r)

The title compound was prepared according to the typical procedure, asdescribed above in 90% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.18 (d, J=8.0, 2H), 7.64-7.60 (m, 4H),7.48-7.447 (m, 2H), 7.41-7.37 (m, 1H), 5.80 (d, J=12.4 Hz, 1H), 5.52 (d,J=12.4 Hz, 1H), 3.93-3.80 (m, 1H), 3.54-3.45 (m, 1H), 3.23 (d, J=14.8Hz, 1H), 2.58 (d, J=14.4 Hz, 1H), 2.25 (s, 3H), 0.80 (t, J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.02, 170.01, 147.67, 141.96, 139.21,129.95, 129.02, 128.84, 124.81, 123.54, 92.49, 81.10, 67.66, 62.51,49.08, 46.59, 26.82, 13.41.

HPLC: Chiralcel OD-H (hexane/i—PrOH=65/35, flow rate 1 mL/min, λ=210nm), t_(R) (major)=6.8 min, t_(R) (minor)=15.6 min; 91% ee.

[α]_(D) ²⁵=19.3 (c=1.2, CHCl₃).

HRMS (EI) calcd for C₂₂H₂₂N₂O₈, m/z 442.1371, found 442.1375.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-hydroxy-3-nitro-4-phenyl-2-(4-(trifluoromethyl)phenyl)-cyclopentanecarboxylate(7j)

The title compound was prepared according to the typical procedure, asdescribed above in 95% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.65-7.58 (m, 6H), 7.49-7.46 (m, 2H),7.42-7.38 (m, 1H), 5.81 (d, J=12.4 Hz, 1H), 5.50 (d, J=12.4 Hz, 1H),3.83-3.77 (m, 1H), 3.73 (d, J=2.0 Hz, 1H), 3.54-3.48 (m, 1H), 3.26 (dd,J=2.4, 14.8 Hz, 1H), 2.58 (d, J=14.8 Hz, 1H), 2.26 (s, 3H), 0.76 (t,J=7.2 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.04, 170.12, 139.36, 138.50, 130.45 (q),129.29, 128.97, 128.76, 125.38 (q), 124.83, 92.61, 81.05, 77.22, 67.70,62.42, 49.22, 46.47, 26.82, 13.15.

HPLC: Chiralpak AS-H (hexane/i—PrOH=80/20, flow rate 1 mL/min, λ=210nm), t_(R) (major)=6.4 min, t_(R) (minor)=14.5 min; 92% ee.

[α]_(D) ²⁵=23.8 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₃H₂₂F₃NO₆, m/z 465.1394, found 465.1395.

(1R,2R,3S,4S)-benzyl-1-acetyl-4-hydroxy-3-nitro-2,4-diphenylcyclopentanecarboxylate(7s)

To a solution of benzyl 2-acetyl-4-oxo-4-phenylbutanoate (1.0 mmol, 2eq) and (E)-(2-nitrovinyl)benzene (0.5 mmol, 1 eq) in toluene (0.5 mL)was added catalyst VI (0.05 mmol, 0.1 eq) at 4° C. The resulting mixturewas stirred for 36 hours. The product was afforded by flash columnchromatography over silica gel (EtOAc: exane=1:5) in 95% yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.40 (d, J=2.0 Hz, 1H), 7.37-7.24 (m, 11H),6.90-6.87 (dd, J=2.4, 7.6 Hz, 2H), 5.79 (d, J=12.4 Hz, 1H), 5.43 (d,J=12.4 Hz, 1H), 4.83 (d, J=12.0 Hz, 1H), 4.16 (d, J=12.0 Hz, 1H), 3.80(s, 1H), 3.26 (d, J=14.8 Hz, 1H), 2.54 (d, J=14.8 Hz, 1H), 2.15 (s, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.17, 170.24, 139.70, 134.23, 133.95,128.88, 128.72, 128.63, 128.59, 128.53, 128.35, 128.29, 124.91, 93.33,81.05, 68.07, 67.90, 49.71, 46.56, 26.97.

HPLC: Chiralcel OD-H (hexane/i—PrOH=85/15, flow rate 1 mL/min, λ=210nm), t_(R) (major)=10.4 min, t_(R) (minor)=13.2 min; 88% ee.

[α]_(D) ²⁵=15.5 (c=1.0, CHCl₃).

HRMS (EI) calcd for C₂₇H₂₅NO₆, m/z 459.1677, found 459.1681.

(1R,2R,3S,4S)-ethyl-1-acetyl-4-(4-chlorophenyl)-4-hydroxy-3-nitro-2-phenylcyclopentanecarboxylate (7x)

To a solution of ethyl 2-acetyl-4-oxo-4-(4-chlorophenyl)-butanoate (1.0mmol, 2 eq) and (E)-(2-nitrovinyl)benzene (0.5 mmol, 1 eq) in toluene(0.5 mL) was added catalyst VI (0.05 mmol, 0.1 eq) at 4° C. Theresulting mixture was stirred for 60 hours. The product was afforded byflash column chromatography over silica gel (EtOAc:Hexane=1:5) in 91%yield.

¹H-NMR (400 MHz, CDCl₃) δ 7.59 (d, J=8.8 Hz, 2H), 7.43-7.28 (m, 7H),5.74 (d, J=12.4 Hz, 1H), 5.41 (d, J=12.4 Hz, 1H), 3.84 (d, J=1.2 Hz,1H), 3.82-3.78 (m, 1H), 3.49-3.41 (m, 1H), 3.22 (d, J=15.2 Hz, 1H), 2.54(d, J=15.2, 1H), 2.25 (s, 3H), 0.76 (s, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ 200.33, 170.30, 138.38, 134.59, 134.09,129.03, 128.67, 128.57, 128.32, 126.52, 93.23, 80.68, 67.62, 62.34,49.50, 46.52, 26.90, 13.24.

HPLC: Chiralcel OD-H (hexane/i—PrOH=85/15, flow rate 1 mL/min, λ=220nm), t_(R) (major)=6.3 min, t_(R) (minor)=9.5 min; 91% ee.

[α]_(D) ²⁵=40.6 (c=1.5, CHCl₃).

HRMS (EI) calcd for C₂₂H₂₂ClNO₆, m/z 431.1132, found 431.1137.

In summary, several cyclization processes based on the use ofunsaturated nitro compounds are provided herein. The first is based onan organocatalytic tandem Michael-Henry reaction. The reaction isefficiently catalyzed by readily available 9-amino-9-deoxyepiquinine(VI) to give synthetically useful, highly functionalized chiralcyclohexanes with four stereogenic centers containing two quaternarystereocenters in good to excellent yields (85-94%), excellentenantioselectivities (97% to >99% ee) and high diastereoselectivities(93:7-99:1 dr). The first highly enantioselective Michael addition ofα-substituted β-ketoesters to nitroolefins catalyzed by VI is presentedand, in particular, the first organocatalytic Henry reaction of commonketones used as acceptors with excellent results. This strategy ofdeveloping a practical and efficient tandem Michael-Henry reaction willhopefully spark more efforts into the designing of such organocatalyticreactions.

The second process is based on a highly enantioselective anddiastereoselective organocatalytic domino double Michael reaction thatprovides expedited access toward highly functionalized cyclopentanederivatives. The structure was confirmed by X-ray analysis of adduct 5g.Simple operational procedures, high yields (81-91%), excellentenantioselectivity (90-97% ee), diastereoselectivities (95:5->99:1 dr),and immense potential of synthetic versatility of the products renderthis new methodology highly appealing for asymmetric synthesis. Furtherapplications of this methodology toward total synthesis of naturalproducts and pharmaceutical agents are currently under activeinvestigation.

The third process provides a facile organocatalytic, enantioselectivesynthesis of highly functionalized chiral cyclopentanes with fourstereogenic centers (two quaternary and two tertiary stereocenters) inexcellent yields (90-95%), enantioselectivities (88-96% ee), andcomplete diastereoselectivities by a domino Michael-Henry reactionstrategy. The domino reaction is efficiently catalyzed by readilyavailable catalyst VI (9-amino-9-deoxyepiquinine) to give syntheticallyvaluable multifunctionalized chiral cyclopentanes, where theorganocatalytic intramolecular Henry reaction of common ketones isemployed for the cyclopentane ring-closing step in excellentstereoselectivities. This domino synthesis is particularly useful innatural product synthesis since many types of biologically activenatural substances are known that bear optically active cyclopentanederivatives. This strategy of developing a practical and efficientdomino Michael-Henry reaction is expected to spark further efforts intothe designing of such organocatalytic domino reactions.

The invention illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by exemplary embodiments and optional features, modificationand variation of the inventions embodied therein herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

Other embodiments are within the following claims. In addition, wherefeatures or aspects of the invention are described in terms of Markushgroups, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group.

1. A process of forming a compound of general formula (33)

wherein R¹ and R² are independently from one another one of a silylgroup, an aliphatic group and an alicyclic group with a main chainhaving 1 to about 20 carbon atoms and 0 to about 7 heteroatoms selectedfrom the group consisting of N, O, S, Se and Si, R³ is one of H, a silylgroup, an aliphatic group, an alicyclic group, an aromatic group, anarylaliphatic group and an arylalicyclic group with a main chain having1 to about 20 carbon atoms and 0 to about 7 heteroatoms selected fromthe group consisting of N, O, S, Se and Si, and R⁴ is one of (i) thegroup —CH═CH—R⁹, wherein R⁹ is one of H, a silyl group, an aliphaticgroup, an alicyclic group, an aromatic group, an arylaliphatic group andan arylalicyclic group with a main chain having 1 to about 20 carbonatoms and 0 to about 7 heteroatoms selected from the group consisting ofN, O, S, Se and Si, (ii) an aromatic group, (iii) an arylaliphatic groupand (iv) an arylalicyclic group, the aromatic, arylaliphatic orarylalicyclic group comprising a main chain having 1 to about 20 carbonatoms and 0 to about 7 heteroatoms selected from the group consisting ofN, O, S, Se and Si, the process comprising: providing a first compoundof the general formula (1),

providing a second compound of the general formula (2)

contacting the first compound of formula (1) and the second compound offormula (2) in the presence of a compound of general formula (X),

wherein R⁶ is one of H, OMe, OH, OTf, SH, and NH₂, R⁷ is one of OH and—N(R⁸)H, wherein R⁸ is one of H, a carbamoyl group, and a thiocarbamoylgroup and

represents one of a single and a double bond, and allowing the first andthe second compound to undergo a reaction for a sufficient period oftime to allow the formation of a compound of general formula (23)


2. The process of claim 1, further comprising contacting the compound ofgeneral formula (23) with a compound of general formula R¹¹—X, wherein Xis one of H, halogen, —CN, —COOR¹³, —COSR¹³—COSeR¹³ and —CONR¹⁴R¹⁵wherein R¹³ is one of halogen, —CN, an aliphatic, an alicyclic, anaromatic, an arylaliphatic, and an arylalicyclic group with a main chainof a length of 1 to about 20 carbon atoms, comprising 0 to about 6heteroatoms selected from the group consisting of N, O, S, Se and Si,and R¹⁴ and R¹⁵ are independent from one another one of H, an aliphatic,an alicyclic, an aromatic, an arylaliphatic, and an arylalicyclic groupwith a main chain of a length of 1 to about 20 carbon atoms, comprising0 to about 6 heteroatoms selected from the group consisting of N, O, S,Se and Si, thereby allowing the formation of a compound of generalformula (33).
 3. The process of claim 1, wherein the compound of generalformula (X) is present in a catalytical amount.
 4. The process of claim1, wherein the process is carried out in a suitable solvent.
 5. Theprocess of any one of claims 1-4, wherein contacting the first compoundof formula (1) and the second compound of formula (2) is carried out ata temperature selected in the range from about −40° C. to about 40° C.6. The process of claim 5, wherein contacting the first compound offormula (1) and the second compound of formula (2) is carried out atambient temperature.
 7. The process of claim 1, wherein the process is aprocess of carrying out an asymmetric reaction, and wherein the compoundof general formula (X) is of one of formulas (XA) and (XB),


8. The process of claim 7, wherein the compound of general formula (X)is of formula (XA), wherein the compound of general formula (33) is acompound of general formula (34)

and wherein allowing the first and the second compound to undergo areaction for a sufficient period of time comprises allowing theformation of a compound of general formula (3)


9. A process of forming a compound of general formula (35)

wherein R¹ and R² are independent from one another one of a silyl group,an aliphatic group and an alicyclic group with a main chain having 1 toabout 20 carbon atoms and 0 to about 7 heteroatoms selected from thegroup consisting of N, O, S, Se and Si, R⁴ is one of (i) the group—CH═CH—R⁹, wherein R⁹ is one of H, a silyl group, an aliphatic group, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group with a main chain having 1 to about 20 carbon atomsand 0 to about 7 heteroatoms selected from the group consisting of N, O,S, Se and Si, (ii) an aromatic group, (iii) an arylaliphatic group and(iv) an arylalicyclic group, the aromatic, arylaliphatic orarylalicyclic group comprising a main chain having 1 to about 20 carbonatoms and 0 to about 7 heteroatoms selected from the group consisting ofN, O, S, Se and Si, and R⁵ is one of H, a silyl group, an aliphaticgroup, an alicyclic group, an aromatic group, an arylaliphatic group andan arylalicyclic group with a main chain having 1 to about 20 carbonatoms and 0 to about 7 heteroatoms selected from the group consisting ofN, O, S, Se and Si, the process comprising: providing a first compoundof the general formula (4),

wherein

indicates that the bond is in any configuration relative to the C═Cbond, providing a second compound of the general formula (2)

contacting the first compound of formula (4) and the second compound offormula (2) in the presence of a compound of general formula (X),

wherein R⁶ is one of H, OMe, OH, OTf, SH, and NH₂, R⁷ is one of OH and—N(R⁸)H, wherein R⁸ is one of H, a carbamoyl group, and a thiocarbamoylgroup and

represents one of a single and a double bond; and allowing the first andthe second compound to undergo a reaction for a sufficient period oftime to allow the formation of a compound of general formula (35). 10.The process of claim 9, wherein the compound of general formula (X) ispresent in a catalytical amount.
 11. The process of claims 9, whereinthe process is carried out in a suitable solvent.
 12. The process ofclaims 9, wherein contacting the first compound of formula (4) and thesecond compound of formula (2) is carried out at a temperature selectedin the range from about −40° C. to about 40° C.
 13. The process of claim12, wherein contacting the first compound of formula (4) and the secondcompound of formula (2) is carried out at ambient temperature.
 14. Theprocess of 9, wherein the process is a process of carrying out anasymmetric reaction, and wherein the compound of general formula (X) isof one of formulas (XA) and (XB),


15. The process of claim 14, wherein the compound of general formula (X)is of formula (XA), wherein the compound of general formula (35) is acompound of general formula (5)

and wherein allowing the first and the second compound to undergo areaction for a sufficient period of time comprises allowing theformation of a compound of general formula (5).
 16. A process of forminga compound of general formula (37)

wherein R¹ and R² are independent from one another one of a silyl group,an aliphatic group and an alicyclic group with a main chain having 1 toabout 20 carbon atoms and 0 to about 7 heteroatoms selected from thegroup consisting of N, O, S, Se and Si, R³ is one of H, a silyl group,an aliphatic group, an alicyclic group, an aromatic group, anarylaliphatic group and an arylalicyclic group with a main chain having1 to about 20 carbon atoms and 0 to about 7 heteroatoms selected fromthe group consisting of N, O, S, Se and Si, R⁴ is one of (i) the group—CH═CH—R⁹, wherein R⁹ is one of H, a silyl group, an aliphatic group, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group with a main chain having 1 to about 20 carbon atomsand 0 to about 7 heteroatoms selected from the group consisting of N, O,S, Se and Si, (ii) an aromatic group, (iii) an arylaliphatic group and(iv) an arylalicyclic group, aromatic group, the aromatic, arylaliphaticor arylalicyclic group comprising a main chain having 1 to about 20carbon atoms and 0 to about 7 heteroatoms selected from the groupconsisting of N, O, S, Se and Si, and R¹¹ is one of (i) H, (ii) a silylgroup, (iii) an aliphatic group, (iv) an alicyclic group, (v) anaromatic group, (vi) an arylaliphatic group, (vii) an arylalicyclic thealiphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic groupcomprising a main chain having 1 to about 20 carbon atoms and 0 to about7 heteroatoms selected from the group consisting of N, O, S, Se and Si,(viii) a carbonate group —O—C(O)—O—R¹⁷ and (ix) a carbamoyl group—O—C(O)—N(R¹⁷)—R¹⁸, wherein R¹⁷ and R¹⁸ are independent from one anotherH or one of an aliphatic, an alicyclic, an aromatic, an arylaliphatic,and an arylalicyclic group with a main chain of a length of 1 to about20 carbon atoms, comprising 0 to about 6 heteroatoms selected from thegroup consisting of N, O, S, Se and Si, the process comprising:providing a first compound of the general formula (6)

providing a second compound of the general formula (2)

contacting the first compound of formula (1) and the second compound offormula (2) in the presence of a compound of general formula (X),

wherein R⁶ is one of H, OMe, OH, OTf, SH, and NH₂, R⁷ is one of OH and—N(R⁸)H, wherein R⁸ is one of H, a carbamoyl group, and a thiocarbamoylgroup and

represents one of a single and a double bond; and allowing the first andthe second compound to undergo a reaction for a sufficient period oftime to allow the formation of a compound of general formula (27)


17. The process of claim 16, further comprising contacting the compoundof general formula (23) with a compound of general formula R¹¹—X,wherein X is one of H, halogen, —CN, —COOR¹³, —COSR¹³—COSeR¹³ and—CONR¹⁴R¹⁵ wherein R¹³ is one of halogen, —CN, an aliphatic, analicyclic, an aromatic, an arylaliphatic, and an arylalicyclic groupwith a main chain of a length of 1 to about 20 carbon atoms, comprising0 to about 6 heteroatoms selected from the group consisting of N, O, S,Se and Si, and R¹⁴ and R¹⁵ are independent from one another one of H, analiphatic, an alicyclic, an aromatic, an arylaliphatic, and anarylalicyclic group with a main chain of a length of 1 to about 20carbon atoms, comprising 0 to about 6 heteroatoms selected from thegroup consisting of N, O, S, Se and Si, thereby allowing the formationof a compound of general formula (37).
 18. The process of claim 16,wherein the compound of general formula (X) is present in a catalyticalamount.
 19. The process of claim 16, wherein the process is carried outin a suitable solvent.
 20. The process of claims 16, wherein contactingthe first compound of formula (1) and the second compound of formula (2)is carried out at a temperature selected in the range from about −40° C.to about 40° C.
 21. The process of claim 20, wherein contacting thefirst compound of formula (6) and the second compound of formula (2) iscarried out at ambient temperature.
 22. The process of claim 16, whereinthe process is a process of carrying out an asymmetric reaction, andwherein the compound of general formula (X) is of one of formulas (XA)and (XB),


23. The process of claim 22, wherein the compound of general formula (X)is of formula (XA), wherein the compound of general formula (37) is acompound of general formula (24)

and wherein allowing the first and the second compound to undergo areaction for a sufficient period of time comprises allowing theformation of a compound of general formula (7)